HETEROBIFUNCTIONAL COMPOUNDS AS p53 ACETYLATORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63/378,418, filed on October 5, 2022 and U.S. Provisional Application No.63/507,944, filed on June 13, 2023, the entire contents of which are hereby incorporated by reference. TECHNICAL FIELD This disclosure relates heterobifunctional compounds, which acetylate p53Y220C and induce downstream anti-tumor signaling pathways, compositions comprising one or more of the heterobifunctional compounds, and methods of use thereof for the treatment of p53Y220C-mediated diseases in a subject in need thereof. The disclosure also relates to methods for designing such heterobifunctional compounds. BACKGROUND p53 is one of the most important tumor suppressor proteins that thwart the progression of cancer by inducing several transcription factors to control cell cycle, apoptosis and DNA repair (1). TP53 gene is mutated in more than 50% of all cancers including breast, lung, liver, and prostate cancer (2). Mutations in p53 can lead to increased invasion, migration, cancer cell survival and metastasis (2). The p53 mutations can be further divided into structural mutations which can lead to improper folding of the protein (such as R175H, G245S and R282W), DNA-contact mutations which can alter the transcription of p53 target genes (such as R248Q, R248W and R273H), and stability related mutations which could make p53 simply unstable and undergo rapid denaturation under physiological conditions (such as Y220C and V157F) (3, 4). Y220C is one of the most common p53 mutations that leads to a cavity formation and decrease in the protein’s thermodynamic stability (5). Several small-molecule ligands that selectively bind p53Y220C and could potentially stabilize p53Y220C have been reported (6 – 9). However, none of them have been approved by the FDA (10). It has also been reported that acetylation of p53 can induce a ferroptosis response and further regulate p53 tumor-suppressive functionality (11). SUMMARY This disclosure concerns the first small-molecule acetylators of p53Y220C, developed by linking a small-molecule binder of p53Y220C with a small-molecule ligand of p300/CBP, which binds the bromo domain of p300/CBP and does not inhibit the acetyltransferase activity of p300/CBP, via various linkers. These novel small-molecule acetylators effectively acetylated p53Y220C and induced downstream anti-tumor signaling pathways. The present disclosure relates generally to heterobifunctional compounds which acetylate p53Y220C and to methods for the treatment of p53Y220C-mediated diseases (i.e., a disease which depends on mutant p53Y220C; depends on mutant p53Y220C activity; or includes reduced levels of p53 acetylation relative to a Y220C mutant tissue of the same species and tissue type). It is important to note that these heterobifunctional compounds, which acetylate p53Y220C, can be significantly more effective therapeutic agents than current p53Y220C small-molecule ligands, which do not increase the p53Y220C acetylation levels. The present disclosure further provides methods for identifying p53Y220C acetylators as described herein. More specifically, the present disclosure provides a heterobifunctional compound that contains a p53Y220C small-molecule binder connected to a small-molecule ligand of a histone acetyltransferase via a linker. In some aspects, the p53 acetylators have the form “PI-linker-AL”, as shown below: wherein PI comprises a p53Y220C small-molecule ligand and AL comprises a small- molecule ligand of a histone acetyltransferase (e.g., CBP/p300). Exemplary p53Y220C small-molecule ligands, exemplary small-molecule ligands of histone acetyltransferases, and exemplary linkers are illustrated below: p53Y220C Ligands (PI). In one refinement, p53Y220C ligands (PI) comprise a moiety of FORMULA 1: FORMULA 1 wherein, the “Linker” moiety of the bivalent compound is attached to N; In an embodiment, R ¹ could also be selected from hydrogen, halogen, oxo, Ph, CN, NO ₂ , OR ¹¹ , SR ¹¹ , NR ¹¹ R ¹² , C(O)R ¹¹ , C(O)OR ¹¹ , C(O)NR ¹¹ R ¹² , S(O)R ¹¹ , S(O) ₂ R ¹¹ , S(O) ₂ NR ¹¹ R ¹² , NR ¹³ C(O)OR ¹¹ , NR ¹³ C(O)R ¹¹ , NR ¹³ C(O)NR ¹¹ R ¹² , NR ¹³ S(O)R ¹¹ , NR ¹³ S(O) ₂ R ¹¹ , NR ¹³ S(O) ₂ NR ¹¹ R ¹² optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R ² is selected from hydrogen, halogen, oxo, Ph, CN, NO ₂ , OR ¹¹ , SR ¹¹ , NR ¹¹ R ¹² , C(O)R ¹¹ , C(O)OR ¹¹ , C(O)NR ¹¹ R ¹² , S(O)R ¹¹ , S(O) ₂ R ¹¹ , S(O) ₂ NR ¹¹ R ¹² , NR ¹³ C(O)OR ¹¹ , NR ¹³ C(O)R ¹¹ , NR ¹³ C(O)NR ¹¹ R ¹² , NR ¹³ S(O)R ¹¹ , NR ¹³ S(O) ₂ R ¹¹ , NR ¹³ S(O) ₂ NR ¹¹ R ¹² optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C3-C8 cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein; R ¹¹ , R ¹² , and R ¹³ are independently selected from hydrogen, optionally substituted C1- C8 alkyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1- C8 alkylaminoC1- C8 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3-20 membered heterocyclyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or R ¹¹ and R ¹² , R ¹¹ and R ¹³ , R ¹² and R ¹³ together with the atom to which they are connected form an optionally substituted 3-20 membered cycloalkyl or heterocyclyl ring; R ³ and R ⁷ , independently selected from hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, and optionally substituted C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl; R ⁴ , R ⁵ and R ⁶ , at each occurrence, are independently selected from hydrogen, halogen, CN, OH, NH ₂ , optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted C ₁ -C ₈ alkoxy C ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ alkylamino C ₁ -C ₈ alkyl, optionally substituted 3-8 membered membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, and optionally substituted C ₁ -C ₈ alkylamino C ₁ -C ₈ alkyl. Small-molecule ligands of histone acetyltransferases Small-molecule ligands of histone acetyltransferases (AL) include, but are not limited to FORMULAE 2A, 2B and 2C: wherein R ¹ , R ² , R ³ and R ⁴ are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C ₁ -C ₆ alkyl, optionally substituted 3 to 6 membered carbocyclyl, and optionally substituted 4 to 6 membered heterocyclyl. Linkers In any of the above-described compounds, the p53Y220C ligand can be conjugated to the acetyltransferase ligand through a linker. The linker can include, e.g., acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic, and/or carbonyl containing groups with different lengths. In an embodiment, the linker is a moiety according to FORMULA 3: wherein A, W, and B, at each occurrence, are independently selected from null, CO, CO ₂ , C(O)NR ¹ , C(S)NR ¹ , O, S, SO, SO ₂ , SO ₂ NR ¹ , NR ¹ , NR ¹ CO, NR ¹ CONR ² , NR ¹ C(S), optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyC ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy,optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₃ - C ₁₃ fused cycloalkyl, optionally substituted C ₃ -C ₁₃ fused heterocyclyl, optionally substituted C ₃ -C ₁₃ bridged cycloalkyl, optionally substituted C ₃ -C ₁₃ bridged heterocyclyl, optionally substituted C ₃ -C ₁₃ spiro cycloalkyl, and optionally substituted C ₃ -C ₁₃ spiro heterocyclyl; wherein R ¹ and R ² are independently selected from hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, and optionally substituted C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl; and m is 0 to 15. In an embodiment, the linker is a moiety according to FORMULA 3A: wherein R ¹ , R ² , R ³ , and R ⁴ , at each occurrence, are independently selected from hydrogen, halogen, CN, OH, NH ₂ , optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, and optionally substituted C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl; A, W, and B, at each occurrence, are independently selected from null, CO, CO ₂ , C(O)NR ⁵ , C(S)NR ⁵ , O, S, SO, SO ₂ , SO ₂ NR ⁵ , NR ⁵ , NR ⁵ CO, NR ⁵ CONR ⁶ , NR ⁵ C(S), optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyC ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₃ - C ₁₃ fused cycloalkyl, optionally substituted C ₃ -C ₁₃ fused heterocyclyl, optionally substituted C ₃ -C ₁₃ bridged cycloalkyl, optionally substituted C ₃ -C ₁₃ bridged heterocyclyl, optionally substituted C ₃ -C ₁₃ spiro cycloalkyl, and optionally substituted C ₃ -C ₁₃ spiro heterocyclyl; wherein R ⁵ and R ⁶ are independently selected from hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, and optionally substituted C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl; m is 0 to 15; n, at each occurrence, is 0 to 15; and o is 0 to 15. In an embodiment, the linker is a moiety according to FORMULA 3B: wherein R ¹ and R ² , at each occurrence, are independently selected from hydrogen, halogen, CN, OH, NH ₂ , and optionally substituted C ₁ -C ₈ alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ - C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, or C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl; A and B, at each occurrence, are independently selected from null, CO, CO ₂ , C(O)NR ³ , C(S)NR ³ , O, S, SO, SO ₂ , SO ₂ NR ³ , NR ³ , NR ³ CO, NR ³ CONR ⁴ , NR ³ C(S), and optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C1- C ₈ alkoxyC ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ - C8 hydroxyalkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₃ -C ₁₃ fused cycloalkyl, optionally substituted C ₃ -C ₁₃ fused heterocyclyl, optionally substituted C ₃ -C ₁₃ bridged cycloalkyl, optionally substituted C ₃ -C ₁₃ bridged heterocyclyl, optionally substituted C ₃ -C ₁₃ spiro cycloalkyl, or C ₃ -C ₁₃ spiro heterocyclyl; wherein R ³ and R ⁴ are independently selected from hydrogen, and optionally substituted C ₁ -C ₈ alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, or C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl; each m is 0 to 15; and n is 0 to 15. In an embodiment, the linker is a moiety according to FORMULA 3C: wherein X is selected from O, NH, and NR ⁷ ; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ , at each occurrence, are independently selected from hydrogen, halogen, CN, OH, NH ₂ , optionally substituted C ₁ -C ₈ alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, and optionally substituted C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl; A and B, at each occurrence, are independently selected from null, CO, NH, NH-CO, CO-NH, CH ₂ -NH-CO, CH ₂ -CO-NH, NH-CO-CH ₂ , CO-NH-CH ₂ , CH ₂ -NH-CH ₂ -CO- NH, CH ₂ -NH-CH ₂ -NH-CO, -CO-NH, CO-NH- CH ₂ -NH-CH ₂ , CH ₂ -NH-CH ₂ , CO ₂ , C(O)NR ⁷ , C(S)NR ⁷ , O, S, SO, SO ₂ , SO ₂ NR ⁷ , NR ⁷ , NR ⁷ CO, NR ⁷ CONR ⁸ , NR ⁷ C(S), optionally substituted C ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyC ₁ -C ₈ alkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₂ -C ₈ alkenyl, optionally substituted C ₂ -C ₈ alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C ₃ - C ₁₃ fused cycloalkyl, optionally substituted C ₃ -C ₁₃ fused heterocyclyl, optionally substituted C ₃ -C ₁₃ bridged cycloalkyl, optionally substituted C ₃ -C ₁₃ bridged heterocyclyl, optionally substituted C ₃ -C ₁₃ spiro cycloalkyl, optionally substituted triazole, methyl triazole and optionally substituted C ₃ -C ₁₃ spiro heterocyclyl; wherein R ⁷ and R ⁸ are independently selected from hydrogen, optionally substituted C ₁ -C ₈ alkyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted C ₃ -C ₈ cycloalkoxy, optionally substituted 3-8 membered heterocyclyl, optionally substituted C ₁ -C ₈ alkoxy, optionally substituted C ₁ -C ₈ alkoxyalkyl, optionally substituted C ₁ -C ₈ haloalkyl, optionally substituted C ₁ -C ₈ hydroxyalkyl, optionally substituted C ₁ -C ₈ alkylamino, and optionally substituted C ₁ -C ₈ alkylaminoC ₁ -C ₈ alkyl; m, at each occurrence, is 0 to 15; n, at each occurrence, is 0 to 15; o is 0 to 15; and p is 0 to 15; and pharmaceutically acceptable salts thereof. In an embodiment, the linker is selected from the group consisting of a ring selected from the group consisting of a 3 to 13 membered ring; a 3 to 13 membered fused ring; a 3 to 13 membered bridged ring; and a 3 to13 membered spiro ring; and pharmaceutically acceptable salts thereof. In an embodiment, the linker is a moiety according to one of FORMULAE C1, C2, C3, C4 and C5:

and pharmaceutically acceptable salts thereof. In an embodiment, the heterobifunctional compound according to the present invention is selected from the group consisting of: NS125-033, NS125-034, NS125-035, NS125- 036, NS125-037, NS131-8, NS131-9, NS131-10, NS131-11 and NS131-12; and pharmaceutically acceptable salts thereof. In an embodiment, the heterobifunctional compound according to the present invention is selected from the group consisting of: NS136-37, NS136-38, NS136-44, NS136-45, NS136-46 and NS136-47; and pharmaceutically acceptable salts thereof. In one embodiment, preferred compounds according to the present invention include: a. 2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin oethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)met hyl)ethan-1- amine (NS131-8). b. 2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpho linoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3 - yl)methyl)ethan-1-amine (NS131-9). c. 2-(2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-mor pholinoethyl)- 1H-benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1 ,2,3-triazol- 1-yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-c arbazol-3- yl)methyl)ethan-1-amine (NS131-10). d. 14-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1-yl)- N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl)-3,6,9, 12- tetraoxatetradecan-1-amine (NS131-11). e. 17-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1-yl)- N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl)-3,6,9, 12,15- pentaoxaheptadecan-1-amine (NS131-12). f. 3-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin oethyl)-lH- benzo[d]imidazol-2- yl)ethyl)-2-fluorophenoxy)methyl)-lH-1,2,3-triazol-1- yl)ethoxy)-N-( (9-ethyl-7-( thiazol-4-yl)-9H-carbazol-3-yl)methyl)-N- methylpropanamide (1) g. 3-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpho linoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3 -yl)methyl)-N- methylpropanamide (2). h. 2-(2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-mor pholinoethyl)- 1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol- 1- yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-car bazol-3- yl)methyl)-N- methylacetamide (3). i. 14-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- 1Jenzo(d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-lH-1,2 ,3-triazol-1- yl)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carlJazol-3-yl)methyl)-N -methyl-3,6,9,12- tetraoxatetradecanamide (4) j. 2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin oethyl)-lH- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-l H-1,2,3-triazol-1- yl)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)met hyl)ethan-1- amine (5). k. 2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpho linoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3 - yl)methyl)ethan-1-amine (6). l. 2-(2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-mor pholinoethyl)- 1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol- 1- yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-car bazol-3- yl)methyl)ethan-1- amine (7). m. 14-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1-yl)- N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl)-3,6,9, 12- tetraoxatetradecan-1-amine (8). n. 17-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzofd]imidazol-2- yl)ethyl)-2-fluorophenoxy)methyl)-lH-1,2,3-triazol-1-yl)- N-((9-ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)methyl)-3,6,9,12,15- pentaoxaheptadecan-1-amine (9). o. 2-(2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-mor pholinoethyl)- 1H-benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1 ,2,3-triazol- 1-yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(4-methylthiophen-2 -yl)-9H- carbazol-3- yl)methyl)ethan-1-amine (13, MS78). In some aspects, this disclosure provides a method of treating the p53Y220C-mediated diseases, the method including administering to a subject in need thereof with an p53Y220C-mediated disease one or more bivalent compounds including an p53Y220C ligand conjugated to a acetylation/stability tag. The p53Y220C-mediated diseases may be a disease resulting from p53Y220C instability. The p53Y220C-mediated diseases can have reduced p53Y220C activity relative to a tissue of the same species and tissue type. Non-limiting examples of p53Y220C-mediated diseases or diseases whose clinical symptoms could be treated by p53Y220C acetylators-mediated therapy include: all solid and liquid cancer, chronic infections that produce exhausted immune response, infection-mediated immune suppression, age-related decline in immune response, age- related decline in cognitive function and infertility. As used herein, the terms “about” and “approximately” are defined as being within plus or minus 10% of a given value or state, preferably within plus or minus 5% of said value or state. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1. Western blot analysis showing that p21 induction of p53Y220C acetylators in BxPC3 cell line. Fig.2. Western blot analysis showing that p53-acetylation of p53Y220C acetylators. Fig. 3. Western blot analysis showing the time-dependent p53Y220C acetylation induced by NS131-10. Fig. 4. The p53Y220C acetylator NS131-10 induces cell death in p53Y220C mutant cancer cell lines. Fig. 5. Design and testing of initial p53Y220C-targeting AceTACs. (A) Crystal 25 structure of the p53Y220C-PK9323 complex (PDB ID: 6SI0). The cross-section of the occupied binding pocket is highlighted and the structure of PK9323 is shown. (B) 35 Crystal structure of the CBP bromodomain-compound 17 complex (PDB ID: 4NR5). The cross-section of the occupied binding pocket is highlighted and the structures of compounds 17 and 33 are also shown. (C) Chemical structure of compounds 1-4. (D) Representative Western blot (WB) results of PK9323 and compounds 1-4 on inducing p21 protein expression from three independent experiments. H1299 (p53Y220C) stable cells were treated with the indicated compounds at the indicated concentrations for 24 h. (E) Chemical structure of compounds 5-9. (F) Representative WB results of compounds 5-9 on inducing p21 protein expression from three independent experiments. NCI- H1299 (p53Y220C) stable cells were treated with the indicated compounds at the indicated concentrations for 24 h. (G) Quantification of p21 induction (from panels 1D and 1F) by PK9323 and compounds 1-9 at 24h time point, following 5 μM treatment (from three independent experiments). (H) Left, representative WB results of the p53K382ac level following the treatment with the indicated compounds at 5 μM for 8 h from three independent experiments. NCI-H1299 (p53Y220C) stable cells were treated with the indicated compounds for 8 h followed by endogenous immunoprecipitation (IP) FLAG pulldown. Right, quantification of the normalized p53K382ac level (p53K382ac level over total p53 protein level) following the treatment with the indicated compounds at 5 μM for 8 h (from three independent experiments). To test these compounds, an NCI-H1299 cell line stably expressing the FLAG tagged p53Y220C mutant, NCI-H1299 (p53Y220C) was generated. The background NCI- H1299 cell line is a p53 null cell line. We observed that compound 3 (PEG-3) and compound 4 (PEG-4) modestly increased p21 expression at 5µM in the NCI-H1299 (p53Y220C) cell line at 24 h while PK9323 and compounds 1 and 2 did not (Fig.5D). The lack of significant effects could be due to that the extra methyl group on the terminal amine and the amide functionality in compounds 1-4 might impact binding of these compounds to p53Y220C, based on the previously reported structure – activity relationship (SAR) results for the PK9323 series. 25, 26 Therefore, a second set of AceTACs, compounds 5-9 was designed, by removing the extra methyl group and amide functionality (Fig. 5E, Scheme S2). Compounds 5-9 increased the expression of p21 by about 2-fold compared to PK9323 at the same concentration (Fig. 5F-G). Particularly, compound 7 (PEG-3) at 5µM induced the most significant acetylation of p53Y220C lysine 382 (p53K382ac) among these compounds (with PK9323 as a control) at 8h treatment (Fig. 5H). Through these initial studies, we demonstrated that our AceTACs can acetylate p53Y220C and induce p21 expression more effectively than the parent p53Y220C binder PK9323. Fig. 6. Discovery and characterization of MS78. (A) Chemical structure of MS78, derived from compound 7. (B) Comparison of the normalized p53K382ac level between compound 7 and MS78 in NCI-H1299 (p53Y220C) cells treated with the indicated compounds at 0, 1, 3 or 10µM for 24h. Results shown are the mean values ±SD from three independent experiments (** P < 0.01). (C) Left, WB results of the p53K382ac level in NCI- H1299 (p53Y220C) cells treated with MS78 at the indicated concentrations at 24h. Results shown are representative of three independent experiments. Right, quantification of the normalized p53K382ac level on the left. Results shown are the mean values ±SD from three independent experiments. (D) WB results of the p53K382ac level in NCI-H1299 (p53Y220C) cells treated with 10 μM MS78 at the indicated time-points. Results shown are representative of three independent experiments. (E) WB result of the p53K382ac level at the indicated time- points post treatment of NCI-H1299 (p53Y220C) cells with MS78 at 10 μM for 6 h. Results shown are representative of three independent experiments. (F) Left, WB results of MS78-mediated p53-p300 interaction via p53-FLAG pull-down in NCI- H1299 (p53-null) and NCI-H1299 (p53Y220C) cells treated with MS78 at the indicated concentrations for 24h. Results shown are representative of three independent experiments. Right, quantification of normalized p300 and p53K382ac levels from three independent experiments shown on the left. (G) Left, WB results of p53-FLAG pull-down after treatment of NCI-H1299 (p53Y220C) cells with MS78 at the indicated concentrations and with control siRNA or p300 siRNA. Results shown are representative of three independent experiments. Right, quantification of normalized p300 and p53K382ac levels from three independent experiments shown on the left. (H) Left, WB results of p53-FLAG pulldown after treatment of NCI-H1299 (p53Y220C) cells with MS78 alone at 1 μM, compound 33 alone at 10 μM, or compound 33 pretreatment at 10 μM for 2h, followed by MS78 treatment at 1 μM for 18h.Results shown are representative of four independent experiments. Right, quantification of the p300 and normalized p53K382ac levels from four independent experiments shown on the left (***P < 0.001). To confirm that MS78 binds and stabilizes the p53Y220C protein, we performed a cellular thermal shift assay (CETSA) in the NCI-H1299 (p53Y220C) cell line. Similar to previous results, DMSO- treated p53Y220C had an aggregation temperature (Tagg) of 39°C ± 2°C (Fig. S2). ²⁷ On the other side, both PK9328 and MS78 increased the Tagg shift by 4°C, suggesting that MS78 maintains a similar binding affinity to p53Y22C and a comparable stabilization of p53Y220C compared to PK9328 (Fig.6C, S2). Furthermore, MS78 binds the bromodomain (BRD) of CBP/p300 with an IC50 of 3.02 ± 0.02 μM in an AlphaScreen binding assay and is selective for the CBP/p300 BRD over a panel of other BRD-containing proteins (Fig. S3). Next, we determined that MS78 induced the p53K382ac level in the NCI-H1299 p53Y220C stable cell line in a concentration-dependent manner with an ACE50 (the concentration at which 50% of p53Y220C is acetylated) of 1.87 ± 0.3 μM with the acetylation level induced by MS78 at 10 μM as the maximum response (Fig. 6C). In addition, MS78 induced p53K382 acetylation in a time-dependent manner (Fig. 6D). MS78 increased the p53K382ac level by about 2-fold as early as 6 h and by about 4-fold within 24 h (Fig. 2D). We also conduct a washout experiment by treating NCI-H1299 (p53Y220C) cells with 10 μM of MS78 for 6 h, then removing MS78 and monitoring the p53K382ac level over time. We found that the p53K382ac level returned to the baseline DMSO level at 8 h post the MS78 removal (Fig. 6E, S4), suggesting that the p53Y220C K382 acetylation induced by MS78 is reversible. It was previously reported that both HDAC6 and SIRT2 can regulate the p53K382ac level. ^{37, 38} Overall, these results demonstrated that MS78 binds p53Y220C and the CBP/p300 bromodomain selectively, and effectively induced p53Y220C K382 acetylation in a concentration- and time- dependent manner. Next, we performed endogenous IP experiments to pull down FLAG-tagged p53Y220C to assess the ternary complex formation between p53Y220C and p300 in the presence of MS78. We treated NCI-H1299 p53-null and NCI-H1299 p53Y220C cells with MS78 at two concentrations. As expected, MS78 induced an interaction between p53Y220C and p300 and induced p53K382ac in a concentration-dependent manner in NCI-H1299 p53Y220C cells, whereas no interaction was observed in NCI-H1299 p53-null cells (Fig. 6F). To further confirm that p53Y220C K382 acetylation depends on p300, we knocked down p300 using siRNA in the NCI-H1299 (p53Y220C) cell line and monitored p53Y220C K382 acetylation. Upon treatment with MS78, there was a concentration-dependent increase in p53K382ac level in control siRNA-treated cells concurrent with the increase in interaction between p53Y220C and p300 (Fig.6G). On the other hand, p53Y220C K382 acetylation was significantly diminished in the p300 siRNA-treated cells (Fig.6G), thereby confirming that the MS78-mediated p53Y200C K382 acetylation is dependent on p300. Finally, we performed competition rescue experiments by pretreating the NCI-H1299 p53Y220C cell line with 10 μM of compound 33 (the p300/CBP bromodomain binder used in MS78) for 2 hours. Compound 33 pretreatment completely abolished p300-p53Y220C interaction and significantly reduced the p53K382ac level induced by MS78 (Fig.2H). Altogether, the FLAG- IP, knockdown and rescue experiments in the isogenic cell lines demonstrated that MS78 can induce ternary complex formation between p53Y220C and p300 and the p53Y200C K382 acetylation induced by MS78 is dependent on p300. It is worth to note that the exact role of CBP is not clear and further investigation is needed in the future. As MS78 effectively induces p53Y220C K382 acetylation in a p300 dependent manner, we hypothesized that the antiproliferative activity of MS78 also depends on the presence of p53Y220C and p300. Therefore, we assessed the effect of MS78 on the cell viability and p53K382ac level in p53-null and p53Y220C-expressing NCI-H1299 isogenic cell lines with PK9328 and compound 33 as controls (Fig.7A-B). As expected, in NCI-H1299 p53-null cells, MS78 as well as PK9328 and compound 33 did not induce any significant cell growth inhibition (Fig. 7A). On the other hand, in NCI- H1299 p53Y220C cells, MS78 concentration-dependently inhibited the cell growth and was more effective than the parent p53Y220C stabilizer PK9328 in inhibiting the cell growth, while compound 33 had no effect (Fig. 7B). We next confirmed that while MS78 did not induce K382 acetylation in NCI-H1299 p53-null cells, it significantly induced K382 acetylation in NCI- H1299 p53Y220C cells (Fig. 7C). As expected, PK9328 and compound 33 did not significantly induced K382 acetylation in either cell line (Fig. 7C). Furthermore, in p53Y220C-expressing NCI- H1299 cells, knockdown of p300 abolished the anti-proliferative effect of MS78 (Fig. 7D-E). Interestingly, PK9328 induced about 50% reduction in the cell growth in p300-siRNA-treated NCI- H1299 p53Y220C cells, confirming that the main mechanism of action of PK9328 is independent on p300 (Fig. 7D-E). We also confirmed that the effect of MS78 on inducing p53 Y220C K382 acetylation was abolished in p300 knockdown cells (Fig. 7F). Overall, these results suggest that the cell growth inhibition effect of MS78 is dependent on p53Y220C and p300. Fig. 7. MS78 inhibits cell growth in NCI-H1299 p53Y220C cells, but not in NCI- H1299 p53- null cells. Cell viability of MS78, PK9328 and compound 33 in (A) NCI- H1299 p53-null and (B) NCI-H1299 p53Y220C cells. The cells were treated with the indicated compounds at the indicated concentrations for 72 h. The mean values ± SD from three independent experiments are shown. (C) Left, representative WB results of the p53K282ac level induced by MS78, PK9328 and compound 33 at 0, 1, 3, 10 μM in NCI-H1299 p53-null and NCI-H1299 p53Y220C cells (24 treatment). Right, quantification of the p53K382ac protein level normalized to Vinculin from two independent experiments. Cell viability of MS78, PK9328 and compound 33 in NCI- H1299 p53Y220C cells treated with (D) control siRNA or (E) p300-siRNA. The cells were treated with siRNA for 72 h and then treated with the indicated compounds at the indicated concentrations for 72 h. The mean values ± SD from three independent experiments are shown. (F) Left, representative WB results of the p53K282ac level in NCI-H1299 p53Y220C cells treated with control siRNA or p300-siRNA and then treated with MS78, PK9328 or compound 33 at 0, 1, 3, 10 μM for 24 h. Right, quantification of the p53K382ac protein level normalized to Vinculin from two independent experiments. Fig. 8. MS78 effectively inhibits cell growth in cancer cell lines that endogenously express p53Y220C and is non-toxic in WT p53 cells. (A) Cell viability results of MS78, PK9328 and compound 33 in BxPC3 cells, which were treated with DMSO or the indicated compounds at the indicated concentrations for 72 h. The mean value ± SD for each concentration point (in technical triplicates from three biological experiments) is shown in the curves. GraphPad Prism 8 was used in analysis of raw data. (B) Clonogenic assay results of MS78, PK9328 and compound 33 in BxPC3 cells treated with DMSO or 1, 3, or 10 μM of the indicated compounds for 14 days. Cells were fixed and stained with crystal violet and the images are representative of two independent experiments. (C) Left: representative WB results of the p53K382ac protein level in BxPC3 cells treated with MS78, PK9328 or compound 33 at 0, 1, 3 or 10 μM for 24 h. Right: quantification of the normalized p53K382ac level in BxPC3 cells from three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001. (D) Cell viability results of MS78, PK9328 and compound 33 in NUGC- 3 cells treated with DMSO or the indicated compounds at the indicated concentrations for 72 h. The mean value ± SD for each concentration point (in technical triplicates from three biological experiments) is shown in the curves. GraphPad Prism 8 was used in analysis of raw data. (E) Clonogenic assay results of MS78, PK9328 and compound 33 in NUGC-3 cells treated with DMSO or 1, 3, or 10 μM of the indicated compounds for 14 days. Cells were fixed and stained with crystal violet and the images are representative of two independent experiments. (F) Left: representative WB results of the p53K382ac protein level in NUGC-3 cells treated with MS78, PK9328 or compound 33 at 0, 1, 3 or 10 μM for 24 h. Right: quantification of the normalized p53K382ac level in NUGC-3 cells from three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001. (G) Cell viability assay results of MS78, PK9328 and compound 33 in U-2 OS cells treated with the indicated compounds at the indicated concentrations for 72 h. The mean value ± SD for each concentration point (in technical triplicates from two biological experiments) is shown in the bar graph. (H) WB results of the p53K382ac protein level in U-2 OS cells treated with MS78, PK9328 or compound 33 at 0, 1, 3 and 10 μM for 24 h. WB results shown are representative of two independent experiments. The tumor-suppressive effect of MS78 in p53Y220C-harboring cancer cell lines was examined. Indeed, MS78 exhibited potent anti-proliferative activity in BxPC3 (p53Y220C/-) cells with a GI50 of 3.3 ± 1 μM and in NUGC-3 (p53Y220C/+) cells with a GI50 of 2.7 ± 0.5 μM (Fig. 4A- F). Importantly, MS78 displayed about 4-fold higher potency compared to the parent compound PK9328 (GI50 of 13.9 ± 2.4 μM in BxPC3; GI50 of 12.6 ± 1.9 μM in NUGC-3 cell line), while compound 33 had minimal antiproliferative activity (Fig. 4A,D). Consistent with the cell viability results, MS78 also showed a marked reduction in clonogenicity in both BxPC3 and NUGC-3 cell lines compared to PK9328 and compound 33 (Fig. 8B,E). The superior anti-proliferative effect of MS78 is likely due to its ability to acetylate p53Y220C K382. Indeed, MS78 induced an about 4- fold increase in the p53K382ac level at 10μM in both BxPC3 and NUGC-3 cell lines (Fig.8C,F). We next assessed toxicity of MS78 in cancer cells with wild type (WT) p53 with PK9328 and compound 33 as controls. In p53 WT U-2OS cancer cells, both MS78 and PK9328 did not significantly inhibited cell growth (GI50 >10 μM) with modest inhibition (30-40%) at the highest concentration tested (10 μM) (Fig.8G). As expected, these compounds did not alter the p53K382ac level (Fig. 8H). Furthermore, because some p53Y220C small-molecule stabilizers were reported to induce cell death in WI38, a normal fibroblast cell line, ^{21, 22, 24} we assessed the cytotoxicity of MS78 in a normal prostate cell line, PNT2. We found that MS78 as well as PK9328 and compound 33 is not toxic in PNT2 cells (GI50 >10 μM) (Fig. S5). Taken together, these results suggest that MS78’s anti-proliferative activity is selective for cancer cells with the Y220C mutation over cancer cells with WT p53 and normal cells, and that MS78 could be a potentially useful tool compound for selectively targeting cancer cells harboring the p53Y220C mutation. It was previously reported that several p53Y220C small-molecule stabilizers could restore the activity of the p53Y220C mutant to WT activity and induce the expression of PUMA, p21, MDM2, NOXA and BAX. ^{23, 24, 27} To compare the effect of p53Y220C K382 acetylation to traditional p53Y220C stabilization on downstream signaling, we performed RT-qPCR to assess changes in the mRNA level of p53-target genes upon MS78 and PK9328 treatment. Similar to the previously reported results, we found that the p53Y220C stabilizer PK9328 upregulated the expression of p21 (CDKN1A) and Mdm2 genes (Fig. S6). On the other hand, MS78 induced less upregulation in CDKN1A and Mdm2 compared to PK9328, while both MS78 and PK9328 had little or modest effect on TIGAR, BAX and PUMA (BBC3) genes (Fig. S6). To better understand the global impact of the p53Y220C acetylation induced by MS78 on downstream signaling, we performed RNA-seq studies in NCI-H1299 p53-null and p52Y220C-expressing isogenic cell lines treated with MS78. Fig.9. The p53Y220C AceTAC MS78 induces downstream signaling of canonical and non-canonical p53 pathways. . (A) Heatmap enrichment in high confidence p53-target genes. NCI- H1299 p53-null and p53Y220C cell lines were treated with DMSO or 10 μM of MS78 for 24 h in quadruplicate. (B) Volcano plot of differential gene expression (DGE) of upregulated protein and pathways upon 10 μM of MS78 treatment compared to DMSO for 24 h in NCI-H1299 p53Y220C cells. (C) Volcano plot of DGE of upregulated protein and pathways upon 10 μM of MS78 treatment in NCI-H1299 p53Y220C cells compared to 10 μM of MS78 treatment in NCI-H1299 p53-null cells and DMSO treatment in both cell lines. (D) Enrichment plot of significant genes upregulated from the 343 high-confidence p53-target genes (q-value < 0.01, normalized enrichment score (NES) = 1.52) in NCI-H1299 p53Y220C cells treated with 10 μM of MS78 versus DMSO for 24 h in quadruplicate. (E) KEGG pathway analysis of upregulated protein and pathways, upon 10 μM of MS78 treatment compared to DMSO for 24 h in NCI-H1299 p53Y220C cells. (F) KEGG pathway analysis of upregulated protein and pathways, upon 10 μM of MS78 treatment in NCI-H1299 p53Y220C stable cell line compared to DMSO treatment in NCI-H1299 p53Y220C cells, DMSO treatment in NCI-H1299 p53-null cells, and 10 μM of MS78 treatment in NCI-H1299 p53-null cells. The values of log2 fold change and log10 p-values in panels B and C were generated from 4 independent experiments. Using the RNA-seq data, we evaluated and identified enrichment in the 343 high confidence p53- target genes previously reported (q-value < 0.01, normalized enrichment score (NES) = 1.52, Fig. 9A-D, S7). ³⁹ We first determined the effect of MS78 on genes regulating the cell cycle process. Similar to the RT-qPCR results, the RNA-seq studies also confirmed the upregulation of p21 gene (CDKN1A) after 10 μM of MS78 treatment for 24 h (Fig. 9A-C). Furthermore, MS78 treatment also led to the upregulation of several cell-cycle arrest genes such as GADD45A and BTG1 which were previously shown to induce G2/M and G1/S cell cycle arrest. ^{40, 41} Finally, we also determined the p53-dependent repression of E2F1, CDC25A, CDK1, and CDK4 genes indicative of the activation of p53-p21-DREAM-E2F/CHR (p53-DREAM) repressor pathway. ^{39, 42} However, the p53Y220C stabilizer PK9328 induced a 12-fold increase in p21 mRNA expression while MS78 induced a 8-fold increase in p21 mRNA expression (Fig. S6), suggesting MS78 may lead to other p53Y220C-mediated transcriptomic changes. Next, we assessed the effect of MS78 on genes regulating apoptosis and found that there was no significant upregulation of BAX, PUMA (BBC3) and NOXA (PMAIP1) genes, consistent with the RT-qPCR results (Fig. S6). However, interestingly, MS78 induced a statistically significant induction of TNF related apoptosis inducing ligand (TRAIL) genes such as TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), and TRAIL-R4 (TNFRSF10D) (log2fold change >2, p-value <0.05) (Fig. 9A, B). It was previously shown that p53 WT has two DNA binding sites on TNFSF10 promoter regions and can regulate TRAIL gene transcription to induce cell death. ⁴³ Furthermore, it was also demonstrated that acetylation of the gain-of-function (GOF) p53 mutant R158G significantly reduced tumor growth in vivo by upregulating TRAIP expression which subsequently suppresses the oncogenic nuclear factor kappa-B (NF-δB) signaling. ⁴⁴ Our results suggest that p53Y220C K382 acetylation may also prompt cell death by inducing the expression of TRAIL genes. While MS78 led to the downregulation of several DDR genes such as ATM, ATR, and CHEK1/2, we also found the upregulation of several heat shock protein genes such as HSPA5, HSP40 (DNAJB1), and HSP1A1/B (Fig. 9B). Together with the upregulation of heme oxygenase 1 (HMOX1) and nuclear protein 1, transcriptional regulator (NUPR1) genes upon MS78 treatment, these data suggest that MS78 may regulate ferroptosis response by upregulating key genes such as HSPA5, HMOX1 and NUPR1. ^{40, 45, 46} Further unbiased analysis using differential gene expression (DGE) and enrichment in KEGG pathways revealed downregulation of the proteins involved in homologous recombination, base excision repair and DNA replication pathway while simultaneously upregulation of protein processing in endoplasmic reticulum (ER) compared to DMSO (Fig. 9E). To determine the p53Y220C-specific effect of MS78, we compared the MS78- mediated DGE in NCI-H1299 p53Y220C cells relative to that in NCI-H1299 p53-null cells and DMSO control in both cell lines (Fig. 9F). Consistently, MS78 upregulated TRAIL and key ferroptosis genes while downregulating the DDR pathway only in the NCI-H1299 p53Y220C cell line, suggesting that these differentially altered pathways are likely due to the p53Y220C acetylation induced by MS78 (Fig. 9F). However, further investigations are needed to validate the downstream targets of the p53Y220C K382 acetylation induced by MS78. Fig.10. WB results of the p53K382ac level after NCI-H1299 (p53Y220C) cells treated with compound 7 or MS78 at 0, 1, 3 or 10 μM for 24 h. Results shown are representative of three independent experiments. Fig. 11. Cellular thermal shift assay (CETSA) results of MS78 amd PK9328 in NCI- H1299 p53Y220C cells. (A) Representative WB results of CETSA in NCI-H1299 (p53Y220C) stable cells treated with DMSO or 100 μM of PK9328 or MS78 for 1 h, and heat treated from 30°C to 50°C. (B) Quantification of the WB results of CETSA shown in Fig.2B in NCI-H1299 (p53Y220C) cells treated with DMSO or 100 μM of PK9328 or MS78 for 1 hour, and heat from 30°C to 50°C. The mean values ± SD of the aggregation temperature (Tagg) for DMSO, PK9328 and MS78 from three independent experiments are shown in the table. Fig. 12. MS78 is selective for the p300/CBP bromodomain over other bromodomain- containing proteins. (A) MS78 binds the p300/CBP bromodomain with an IC50 of 3.02 ± 0.02 μM (n = 2) in an AlphaScreen binding assay. (B) MS78 does not bind other bromodomain-containing proteins significantly in a BromoMELT ^™ Assay (Reaction Biology Corp.) Results shown are the mean values from duplicate experiments. Fig. 13. Quantification of WB results of the normalized p53K382ac level in Fig. 2E from three independent experiments. Fig.14. MS78 does not significantly inhibits the growth in PNT2 normal prostate cells. PNT2 cells were treated with the indicated compounds at the indicated concentrations for 72 h. The mean value ± SD for each concentration point (in technical triplicates from three biological experiments) is shown in the bar graph. Fig. 15. RT-qPCR analysis of relative mRNA levels of p53-target genes. NCI-H1299 p53Y220C stable cells were treated with DMSO, PK9328 or MS78 at 10 µM for 24 h. The mRNA expression for each target gene was first normalized to internal GAPDH and then calculated relative to the DMSO control. The mean value ± SD for each gene (in technical triplicates from three biological experiments) is shown. ** P < 0.01, *** P < 0.001 , ns: not significant. Fig.16. Enrichment plot of significant genes in 343 high-confidence p53 target genes after differential gene expression upon 10 μM of MS78 treatment in NCI-H1299 p53Y220C stable cell line compared to DMSO treatment in NCI-H1299 p53Y220C cells, DMSO treatment in NCI- H1299 p53-null cells, and 10 μM of MS78 treatment in NCI-H1299 p53-null cells. Q-value = 0.045, normalized enrichment score (NES) = 1.32. The q-value and NES score were generated from 4 independent experiments. Fig.17. ¹ H NMR spectrum of MS78. Fig.18. ¹³ C NMR spectrum of MS78. Fig.19. LC-MS spectrum of MS78. Fig.20 shows the structure and binding of compound MS78. DETAILED DESCRIPTION The present disclosure is based, in part, on the discovery that novel heterobifunctional molecules which acetylate p53Y220C and are useful in the treatment of p53Y220C- mediated diseases. Non-limiting examples of p53Y220C-mediated diseases or diseases whose clinical symptoms could be treated by p53Y220C acetylators-mediated therapy include: all solid and liquid cancer, chronic infections that produce exhausted immune response, infection-mediated immune suppression, age-related decline in immune response, age- related decline in cognitive function and infertility Exemplary type of cancers that could be prevented, or therapeutically treated by p53Y220C acetylators include all solid and liquid cancers, including, but not limited to, cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Examples of liquid cancers include lymphomas, sarcomas, and leukemias. Listed below are the type of cancers that immunotherapy using p53Y220C acetylators should be able to prevent or treat. Examples of breast cancers include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Examples of ovarian cancer include, but are not limited to, serous tumor, endometrioid tumor, mucinous cystadenocarcinoma, granulosa cell tumor, Sertoli-Leydig cell tumor and arrhenoblastoma. Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, glassy cell carcinoma and villoglandular adenocarcinoma. Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Examples of esophageal cancer include, but are not limited to, esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma. Examples of gastric cancer include, but are not limited to, intestinal type and diffuse type gastric adenocarcinoma. Examples of pancreatic cancer include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumors. Example of tumors of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Examples of kidney cancer include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumor. Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma. Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Example of skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Example of head-and-neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell. Example of lymphomas include, but are not limited to, AIDS-related lymphoma, non- Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system. Example of sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Example of leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. The p53Y220C stabilizers/ acetylators should be able to treat the above cancer type as stand alone agent or used as agent in combination with existing standard of treatment therapy and other FDA-approved cancer therapy. EXAMPLES The following Examples describe the synthesis of exemplary p53Y220C acetylators compounds according to the present invention. Example 1: Synthesis of Intermediate 1 NS121-183 To a stirred solution of 2-bromo-9H-carbazole (5 g, 20.3 mmol) in DMF (20 mL), sodium hydride (1.625 g, 40.6 mmol, 2 equiv.) was added at room temperature and stirred for 30 min at rt. Then iodoethane (3.27 mL, 40.6 mmol, 2 equiv.) was added to the mixture at room temperature and stirred for 16 h at rt. The mixture was diluted by ethyl acetate and water, extracted by ethyl acetate, dried by anhydrous sodium sulfate. The solvent was removed in vacuo to afford the product as a white solid without further purification. To a flask of DMF (10 mL) under argon at 0 °C was added POCl ₃ (9.3 g, 60.9 mmol, 3 equiv.) dropwise. Then remove the ice bath. To the resulting solution was added a solution of 2-bromo-9-ethyl-9H-carbazole (last step, 20.3 mmol) in DMF (10 mL) dropwise at room temperature. Then the mixture was heated at 80 °C for 18 h, and the mixture was poured in ice water. The solution was neutralized by addition of 10% NaOH aqueous solution, extracted by ethyl acetate, washed with brine, dried by anhydrous sodium sulfate and chromatographed on silica gel (0% to 25% ethyl acetate in hexanes) to afford the desired product as a beige flocculent solid (4.42 g, 72% two step yield). To a solution of 7-bromo-9-ethyl-9H-carbazole-3-carbaldehyde (1.5 g, 5 mmol), bispinacolato diboron (1.9 g, 7.5 mmol) and potassium acetate (1.47 g, 15 mmol) in 1,4-dioxane (12 mL) under argon was added Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (408 mg, 0.5 mmol). The resulting solution was stirred at 80 °C for 12 h. The solution was cooled and H ₂ O was added. Crude product was extracted with ethyl acetate. The organic extracts were washed with brine then dried by anhydrous anhydrous sodium sulfate. The suspension was chromatographed on silica gel (25% ethyl acetate in hexanes) to afford the product as a pale yellow solid (1.43 g, 82% yield). To a tube was added 9-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H- carbazole-3-carbaldehyde (470 mg, 1.34 mmol), 4-bromothiazole (100 µL, 1.12 mmol), potassium carbonate (308 mg, 2.23 mmol) and Pd-118 (36 mg, 0.05 mmol). The tube was evacuated and backfilled with argon three times before anhydrous acetonitrile (5 mL) and degassed H ₂ O (5 mL) were added. The solution was heated to 80 °C and stirred for 2 h. The reaction was cooled to room temperature and diluted with ethyl acetate and H ₂ O. Crude product was extracted with ethyl acetate, washed with brine and dried by anhydrous anhydrous sodium sulfate. The suspension was filtered and the filtrate was concentrated under a reduced pressure to yield crude product that was purified by chromatography on silica gel (20-50% ethyl acetate in hexanes). Product Intermediate 1 NS121-1839-ethyl-7-(thiazol-4-yl)-9H-carbazole-3-carbaldehyd e was isolated as a yellow solid (342 mg, 79% yield). ¹ H NMR (600 MHz, Chloroform-d) δ 10.09 (s, 1H,), 8.57 (s, 1H), 8.10 (d, J = 8.2 Hz, 1HH), 7.98 (d, J = 8.6 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.13 (t, J = 4.4 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C18H15N2OS ⁺ [M + H] ⁺ , 307.09; found, 307.12.

Example 2 Synthesis of Intermediate 2 NS125-025 Intermediate 1 9-Ethyl-7-(thiazol-4-yl)-9H-carbazole-3-carbaldehyde (342 mg, 1.11 mmol), methylamine (836 µL, 1.67 mmol), anhydrous THF (15 mL) and sodium triacetoxyborohydride (591 mg, 2.79 mmol). The reaction was stirred at rt for 12 h. The mixture was purified by reverse C18 column (eluent: with 10%-100% (v1:v2) acetonitrile in water (contain 0.1% trifluoroacetic acid)) to give the 1-(9-ethyl-7- (thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine Intermediate 2 NS125-025 as a white solid (184 mg, 51%). ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.13 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H), 8.20 – 8.17 (m, 2H), 8.02 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.1, 1.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 8.4, 1.8 Hz, 1H), 4.54 (q, J = 7.2 Hz, 2H), 4.36 (s, 2H), 2.76 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C ₁₉ H ₂₀ N ₃ S ⁺ [M + H] ⁺ , 322.14; found, 322.12.

Example 3 Synthesis of Intermediate 3 To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4- dihydroquinolin-1(2H)-yl)-1-(piperidin-4-yl)-1,4,6,7-tetrahy dro-5H-pyrazolo[4,3- c]pyridine-5-carboxylate (57 mg, 0.1 mmol) and DIEA (39 mg, 0.3 mmol) in DCM (2 mL) was added Fmoc-Cl (28 mg, 0.11 mmol) slowly at 0 °C. The mixture was stirred at 25 °C for 1 h, before it was concentrated in vacuo. The residue was purified by reverse phase C18 column (10% - 100% methanol / 0.1% TFA in water) to afford the compound tert-butyl 1-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)-3-( 7- (difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroqui nolin-1(2H)-yl)- 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 63%). MS (ESI) m/z = 790.5 [M+H] ⁺ . To a solution of tert-butyl 1-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)- 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihyd roquinolin-1(2H)-yl)- 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (50 mg, 0.063 mmol) in DCM (1.5 mL) was added TFA (0.3 mL). After being stirred for 1 h at rt, the reaction mixture was concentrated and the residue was purified by reverse phase C18 column (10% - 100% methanol / 0.1% TFA in water) to afford the compound (9H-fluoren-9- yl)methyl4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-y l)-3,4- dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3 -c]pyridin-1- yl)piperidine-1-carboxylate (32 mg, 74%). MS (ESI) m/z = 690.6 [M+H] ⁺ . (9H-fluoren-9-yl)methyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4- dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3 -c]pyridin-1- yl)piperidine-1-carboxylate (28 mg, 0.04 mmol) was dissolved in DCM (1 mL). DIEA and N-methyl-1H-imidazole-1-carboximide was added at rt and stirred overnight. The mixture was concentrated in vacuo and purified by reverse phase C18 column (10% - 100% methanol / 0.1% TFA in water) to afford the compound (9H-fluoren-9-yl)methyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-di hydroquinolin-1(2H)- yl)-5-(methylcarbamoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c ]pyridin-1- yl)piperidine-1-carboxylate (25 mg, 84%). MS (ESI) m/z = 747.3 [M+H] ⁺ . To a solution of (9H-fluoren-9-yl)methyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H- pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-5-(methylcarbamo yl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (25 mg, 0.033mmol) in DMF (1 mL) was added piperidine (5 drops). After being stirred at rt for 1.5 h. The mixture was purified by reverse phase C18 column (10% - 100% methanol / 0.1% TFA in water) to afford the compound Intermediate 3 3-(7-(difluoromethyl)-6-(1-methyl-1H- pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(pipe ridin-4-yl)-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (12 mg, 71%). ¹ H NMR (600 MHz, CD ₃ OD) δ 7.67 (s, 1H), 7.54 (s, 1H), 7.12 (s, 1H), 6.76 (s, 1H), 6.60 (t, J = 55.4 Hz, 1H), 4.53 – 4.45 (m, 1H), 4.11 (s, 2H), 3.95 (s, 3H), 3.75 (t, J = 5.8 Hz, 2H), 3.69 (t, J = 5.7 Hz, 2H), 3.63 – 3.56 (m, J = 13.2, 3.8 Hz, 2H), 3.23 (td, J = 12.8, 3.2 Hz, 2H), 2.92 (t, J = 6.2 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 2.70 (s, 3H), 2.37 – 2.28 (m, 2H), 2.25 – 2.19 (m, J = 14.4, 3.8 Hz, 2H), 2.13 – 2.08 (m, 2H). MS (ESI) m/z = 525.6 [M+H] ⁺ General procedure A for the synthesis of p53Y220C acetylators. To a solution of azido-acid terminal substituted linkers (0.05 mmol, 1 equiv) in DMF (1 mL) were added Intermediate 2 (0.05 mmol, 1.0 equiv), HOAt (1-hydroxy-7- azabenzo-triazole) (0.1 mmol, 1.2 equiv), EDCI (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide) (0.1 mmol, 1.2 equiv), and NMM (N- methylmorpholine) (0.25 mmol, 5 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% acetonitrile/ 0.1% TFA in H ₂ O), the solvent was evaporated under the reduced pressure. Then to a stirred solution of 4-(2-(2-(3-fluoro-4-(prop-2-yn-1-yloxy)phenethyl)-5- phenyl-1H-benzo[d]imidazol-1-yl)ethyl)morpholine (0.012 mmol, 1.0 equiv.) in DMF (0.6 mL) and water (0.3 mL) were added last step product (0.012 mmol, 1.0 equiv.), CuSO ₄ .5H ₂ O (5.0 mg, 0.012 mmol, 1.0 equiv.), sodium ascorbate (4.0 mg, 0.012 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 2 h. When the reaction was complete, the crude mixture was purified by preparative HPLC (eluent: with 10%-100% acetonitrile in water which contains 0.1% trifluoroacetic acid), dried by lyophilization to afford the final p53 acetylator. General procedure B for the synthesis of p53Y220C acetylators. To a stirred solution of 4-(2-(2-(3-fluoro-4-(prop-2-yn-1-yloxy)phenethyl)-5-phenyl- 1H-benzo[d]imidazol-1-yl)ethyl)morpholine (0.08 mmol, 1.0 equiv.) in DMF (0.6 mL) and water (0.3 mL) were added azido-amine terminal substituted linkers (0.08 mmol, 1.0 equiv.), CuSO ₄ .5H ₂ O (5.0 mg, 0.08 mmol, 1.0 equiv.), sodium ascorbate (4.0 mg, 0.08 mmol, 1.0 equiv.). Then the resulting mixture was stirred at room temperature for 2 h. When the reaction was complete, the crude mixture was purified by preparative HPLC (eluent: with 10%-100% acetonitrile in water which contains 0.1% trifluoroacetic acid), the solution was evaporated under the reduced pressure. Then to a solution of last step product (0.01 mmol, 1 equiv) in methanol (1 mL) was added Intermediate 1 (0.01 mmol, 1.0 equiv), 3 drops Et ₃ N, then 5 drops acetic acid. Then the reaction was stirred at rt for 1h. Sodium cyanoborohydride (0.05 mmol, 5 equiv). After being stirred for 2 h at rt, the resulting mixture was purified by preparative HPLC (10%-100% acetonitrile/ 0.1% TFA in H ₂ O), dried by lyophilization to afford the final p53 acetylator. General procedure C for the synthesis of p53Y220C acetylators. H N CHO NH X 2 X ^{CO tBu} n H N ² n _TFA COOH N H N F N N c) ₃ BH ₃ D N F N ^N Na(OA CM N N Et _O N S Et MeOH S N I ^{ntermediate 1} HN _{Intermediate 3} O N O HOAt, EDCI N N X n N NMM N H N N DMF, rt S N F Et F N _N To a solution of amine-based linkers (0.05 mmol, 1 equiv) in methanol (1 mL) were added Intermediate 1 (0.05 mmol, 1.0 equiv), 5 drops AcOH, sodium cyanoborohydride (0.1 mmol, 2 equiv). After being stirred 1 h at rt, the resulting mixture was purified by preparative HPLC (10%-100% acetonitrile/ 0.1% TFA in H ₂ O), the solution was evaporated under the reduced pressure. Then the residue were added DCM (1 mL) and TFA (1 mL), stirred at rt for 1h. The mixture was evaporated under the reduced pressure. Then to a solution of last step product (0.01 mmol, 1 equiv) in DMF (1 mL) were added Intermediate 3 (0.01 mmol, 1.0 equiv), HOAt (1-hydroxy- 7-azabenzo-triazole) (2.7 mg, 0.02 mmol, 2 equiv), EDCI (1-ethyl-3-(3- dimethylaminopropyl)carbodiimide) (3.9 mg, 0.02 mmol, 2 equiv), and NMM (N- methylmorpholine) (5 mg, 0.05 mmol, 5 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% acetonitrile/ 0.1% TFA in H ₂ O), dried by lyophilization to afford the final p53 acetylator. Example 4 Synthesis of NS125-033 3-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin oethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)met hyl)-N- methylpropanamide (NS125-033). NS125-033 was synthesized following the standard procedure A. To a solution of Intermediate 2 (16.1 mg, 0.05 mmol, 1 equiv) in DMF (1 mL) were added 3-(2-azidoethoxy)propanoic acid (8.0 mg, 0.05 mmol, 1.0 equiv), HOAt (1-hydroxy-7-azabenzo-triazole) (13.6 mg, 0.1 mmol, 2 equiv), EDCI (1- ethyl-3-(3-dimethylaminopropyl)carbodiimide) (19.2 mg, 0.1 mmol, 2 equiv), and NMM (N-methylmorpholine) (25 mg, 0.25 mmol, 5 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% acetonitrile / 0.1% TFA in H ₂ O) to afford the intermediate as a colorless oil (14.1 mg, 61%). To a solution of 4-(2-(2-(3-fluoro-4-(prop-2-yn-1- yloxy)phenethyl)-5-phenyl-1H-benzo[d]imidazol-1-yl)ethyl)mor pholine (5.6 mg, 0.012 mmol, 1.0 equiv.) in DMF (0.6 mL) and water (0.3 mL) were added last step product (6.0 mg, 0.012 mmol, 1.0 equiv.), CuSO ₄ .5H ₂ O (3 mg, 0.012 mmol, 1.0 equiv.), sodium ascorbate (2.4 mg, 0.012 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 12 h. When the reaction was complete, the crude mixture was purified by preparative HPLC (eluent: with 10%-100% acetonitrile in water which contains 0.1% trifluoroacetic acid), dried by lyophilization to afford NS125-033 as a white solid (5.5 mg, 42%). ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.08 (d, J = 1.9 Hz, 1H), 8.10 – 8.03 (m, 2H), 8.00 – 7.86 (m, 4H), 7.76-7.71 (m, 1H), 7.67 (dd, J = 9.0, 1.5 Hz, 1H), 7.52 (td, J = 8.5, 1.5 Hz, 1H), 7.49-7.45 (m, 1H), 7.35-7.30 (m, 1H), 7.03 – 6.95 (m, 2H), 6.86-6.81 (m, 1H), 5.01 (d, J = 11.7 Hz, 2H), 4.75 (d, J = 8.0 Hz, 2H), 4.66-4.61 (m, 2H), 4.58 – 4.54 (m, 2H), 4.46-4.43 (m, 2H), 3.90 – 3.87 (m, 1H), 3.86 – 3.76 (m, 6H), 3.43-3.38 (m, 2H), 3.30 – 3.15 (m, 4H), 3.14 – 3.03 (m, 5H), 2.97 (s, 3H), 2.76-2.71 (m, 2H), 2.42 (d, J = 1.4 Hz, 3H), 2.26 (d, J = 1.1 Hz, 3H), 1.44-1.38 (m, 3H). LRMS (ESI) m/z: calcd for C53H58FN10O5S ⁺ [M + H] ⁺ , 965.43; found, 965.45. Example 5 Synthesis of NS125-034 3-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpho linoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3 -yl)methyl)-N- methylpropanamide (NS125-034). NS125-034 was synthesized following the standard procedure for preparing NS125-033 from Intermediate 2 and 3-(2-(2- azidoethoxy)ethoxy)propanoic acid. (white solid, 5.2 mg, 39%) ¹ H NMR (600 MHz, Methanol-d4) δ 9.08 (d, J = 2.0 Hz, 1H), 8.14 – 8.06 (m, 2H), 8.04 – 7.87 (m, 4H), 7.76- 7.72 (m, 1H), 7.69 – 7.65 (m, 1H), 7.55 – 7.51 (m, 1H), 7.50 – 7.43 (m, 1H), 7.38-7.34 (m, 1H), 7.09 – 7.03 (m, 1H), 7.02 – 6.97 (m, 1H), 6.91 – 6.83 (m, 1H), 5.09-5.04 (m, 2H), 4.77-4.73 (m, 2H), 4.71 – 4.64 (m, 2H), 4.48-4.45 (m, 4H), 3.86 – 3.74 (m, 6H), 3.59 – 3.53 (m, 3H), 3.44-3.41 (m, 2H), 3.28 – 3.22 (m, 2H), 3.15 – 3.10 (m, 4H), 2.99- 2.96 (m, 3H), 2.79 – 2.68 (m, 2H), 2.66 (s, 5H), 2.42 (d, J = 5.6 Hz, 3H), 2.26 (d, J = 4.5 Hz, 3H), 1.41 (dt, J = 9.0, 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C55H62FN10O6S ⁺ [M + H] ⁺ , 1009.46; found, 1009.43. Example 6 Synthesis of NS125-035 2- (2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morph olinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-car bazol-3-yl)methyl)- N-methylacetamide (NS125-035). NS125-035 was synthesized following the standard for preparing NS125-033 from Intermediate 2 and 2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)acetic acid. (white solid, 5.9 mg, 43%) ¹ H NMR (600 MHz, Methanol-d4) δ 9.09 (dd, J = 5.0, 1.9 Hz, 1H), 8.11 – 7.83 (m, 6H), 7.75 – 7.62 (m, 2H), 7.53 – 7.44 (m, 2H), 7.41 – 7.33 (m, 1H), 7.12-7.08 (m, 1H), 7.03 – 6.97 (m, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.16-5.11 (m, 2H), 4.71 (d, J = 9.5 Hz, 2H), 4.64-4.61 (m, 2H), 4.54 – 4.40 (m, 4H), 4.36-4.33 (m, 2H), 3.82 (t, J = 5.0 Hz, 4H), 3.72 – 3.62 (m, 3H), 3.60 – 3.51 (m, 4H), 3.50 – 3.41 (m, 2H), 3.32 (s, 4H), 3.27 – 3.05 (m, 7H), 2.98-2.94 (m, 3H), 2.40 (d, J = 7.0 Hz, 3H), 2.24 (d, J = 5.8 Hz, 3H), 1.44-1.38 (m, 3H). LRMS (ESI) m/z: calcd for C56H64FN10O ₇ S ⁺ [M + H] ⁺ , 1039.47; found, 1039.49. Example 7 Synthesis of NS125-036 14-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1-yl)-N- ((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl)-N-methyl -3,6,9,12- tetraoxatetradecanamide (NS125-036). NS125-036 was synthesized following the standard for preparing NS125-033 from Intermediate 2 and 14-azido-3,6,9,12- tetraoxatetradecanoic acid. (white solid, 6.4 mg, 45%) ¹ H NMR (600 MHz, Methanol- d ₄ ) δ 9.09 (dd, J = 4.0, 2.0 Hz, 1H), 8.13 – 7.94 (m, 5H), 7.90-7.85 (m, 1H), 7.76 – 7.63 (m, 2H), 7.54 – 7.44 (m, 2H), 7.41 – 7.34 (m, 1H), 7.11 (q, J = 8.3 Hz, 1H), 7.09 – 7.00 (m, 1H), 6.90 (t, J = 9.1 Hz, 1H), 5.18-5.13 (m, 2H), 4.73 (d, J = 10.9 Hz, 2H), 4.68- 4.63 (m, 2H), 4.55 – 4.41 (m, 4H), 4.39-4.36 (m, 2H), 3.87 – 3.74 (m, 5H), 3.70 – 3.56 (m, 4H), 3.55 – 3.39 (m, 8H), 3.36 (t, J = 7.7 Hz, 4H), 3.28 – 3.07 (m, 7H), 2.99-2.96 (m, 3H), 2.40 (d, J = 8.3 Hz, 3H), 2.24 (d, J = 7.5 Hz, 3H), 1.46 – 1.37 (m, 3H). LRMS (ESI) m/z: calcd for C58H68FN10O8S ⁺ [M + H] ⁺ , 1083.49; found, 1083.44. Example 8 Synthesis of NS125-037 5-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoet hyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1-yl)-N- ((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl)-N-methyl pentanamide (NS125-037). NS125-037 was synthesized following the standard for preparing NS125-033 from Intermediate 2 and 5-azidopentanoic acid. (white solid, 5.2 mg, 41%) ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.10 (d, J = 2.1 Hz, 1H), 8.13 – 7.93 (m, 5H), 7.89- 7.86 (m, 1H), 7.78-7.74 (m, 1H), 7.66 (d, J = 13.2 Hz, 1H), 7.56 – 7.46 (m, 2H), 7.36- 7.32 (m, 1H), 7.11 (t, J = 8.5 Hz, 1H), 7.06-7.01 (m, 1H), 6.93 – 6.88 (m, 1H), 5.16- 5.11 (m, 2H), 4.76 (d, J = 21.0 Hz, 2H), 4.57 – 4.35 (m, 6H), 3.73 (s, 3H), 3.49 – 3.40 (m, 3H), 3.22 – 3.14 (m, 2H), 3.01 (d, J = 8.2 Hz, 3H), 2.86 (s, 4H), 2.58-2.53 (m, 2H), 2.42 (d, J = 3.0 Hz, 3H), 2.26 (d, J = 2.2 Hz, 3H), 2.03 – 1.92 (m, 2H), 1.67-1.63 (m, 2H), 1.42 (q, J = 7.3 Hz, 3H). LRMS (ESI) m/z: calcd for C53H58FN10O ₄ S ⁺ [M + H] ⁺ , 949.43; found, 949.45. Example 9 Synthesis of NS131-8 2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin oethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)met hyl)ethan-1-amine (NS131-8). NS131-8 was synthesized following the standard procedure B. To a solution of 4-(2-(2-(3-fluoro-4-(prop-2-yn-1-yloxy)phenethyl)-5-phenyl-1 H-benzo[d]imidazol- 1-yl)ethyl)morpholine (40 mg, 0.08 mmol, 1.0 equiv.) in DMF (0.6 mL) and water (0.3 mL) were added 2-(2-azidoethoxy)ethan-1-amine (10.4 mg, 0.08 mmol, 1.0 equiv.), CuSO ₄ .5H ₂ O (20 mg, 0.08 mmol, 1.0 equiv.), sodium ascorbate (16 mg, 0.08 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 12 h. When the reaction was complete, the crude mixture was purified by preparative HPLC (eluent: with 10%-100% acetonitrile in water which contains 0.1% trifluoroacetic acid) to afford the intermediate as a colorless oil (26.4 mg, 52%). To a solution of last step product (7.5 mg, 0.01 mmol, 1.0 equiv.) in methanol (1 mL) were added intermediate 1 (3.1 mg, 0.01 mmol, 1.0 equiv.), 3 drops Et3N, then 5 drops AcOH. Then the reaction was stirred at rt for 1h. Sodium cyanoborohydride (3.1 mg, 0.05 mmol, 5.0 equiv.) was added. After being stirred for 2 h at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% acetonitrile / 0.1% TFA in H ₂ O) to give the compound NS131-8 (white solid, 4.3 mg, 41%). ¹ H NMR (600 MHz, Methanol-d4) δ 9.12 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.17 (dd, J = 4.7, 3.3 Hz, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.2, 1.3 Hz, 1H), 7.65 – 7.56 (m, 3H), 7.48 (s, 1H), 7.05 (s, 1H), 6.72 (s, 1H), 6.57 (t, J = 55.5 Hz, 3H), 4.59 (d, J = 13.5 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.45 (s, 2H), 4.27 (dt, J = 11.1, 5.8 Hz, 1H), 4.06 (s, 2H), 3.99 (d, J = 15.3 Hz, 1H), 3.91 (s, 3H), 3.83 – 3.77 (m, 2H), 3.73 – 3.44 (m, 17H), 3.30 (s, 6H), 3.13 (t, J = 12.7 Hz, 1H), 2.84 (t, J = 6.5 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 2.69 (s, 3H), 2.66 – 2.60 (m, 1H), 2.52 – 2.46 (m, 1H), 2.07 – 1.83 (m, 6H), 1.44 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C51H56FN10O ₄ S ⁺ [M + H] ⁺ , 922.41; found, 922.44. Example 10 Synthesis of NS131-9 2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpho linoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3 -yl)methyl)ethan-1- amine (NS131-9). NS131-9 was synthesized following the standard for preparing NS131-8 from Intermediate 1 and 2-(2-(2-azidoethoxy)ethoxy)ethan-1-amine. (white solid, 4.2 mg, 39%) ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.09 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 1.7 Hz, 1H), 8.15 (dd, J = 4.7, 3.3 Hz, 2H), 8.05 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.84 – 7.81 (m, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.55 (ddd, J = 8.6, 4.3, 1.6 Hz, 2H), 7.06 – 7.01 (m, 2H), 6.91 (dt, J = 8.3, 1.5 Hz, 1H), 5.05 (s, 2H), 4.75 (t, J = 7.5 Hz, 2H), 4.57 (t, J = 5.0 Hz, 2H), 4.50 (q, J = 7.2 Hz, 2H), 4.39 (s, 2H), 3.92 (t, J = 5.0 Hz, 2H), 3.86 (t, J = 4.7 Hz, 4H), 3.71 – 3.61 (m, 6H), 3.45 (t, J = 7.8 Hz, 2H), 3.34 (s, 2H), 3.25 – 3.09 (m, 8H), 2.43 (s, 3H), 2.27 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C53H60FN10O5S ⁺ [M + H] ⁺ , 967.44; found, 967.39. Example 11 Synthesis of NS131-10 S N N H N O _O N _N O N O F N O N N N O 2-(2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-mor pholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-car bazol-3- yl)methyl)ethan-1-amine (NS131-10). NS131-10 was synthesized following the standard for preparing NS131-8 from Intermediate 1 and 2-(2-(2-(2- azidoethoxy)ethoxy)ethoxy)ethan-1-amine. (white solid, 5.8 mg, 51%) ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.10 (q, J = 2.0 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.15 (q, J = 3.6 Hz, 2H), 8.02 – 7.95 (m, 2H), 7.93 (dd, J = 8.5, 3.2 Hz, 1H), 7.82 (dd, J = 8.7, 3.1 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.62 – 7.51 (m, 3H), 7.07 (ddt, J = 10.9, 7.3, 4.1 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 3.1 Hz, 2H), 4.71 (d, J = 7.1 Hz, 2H), 4.56 – 4.36 (m, 6H), 3.88 – 3.73 (m, 7H), 3.66 – 3.43 (m, 11H), 3.29 – 2.98 (m, 10H), 2.43 (s, 3H), 2.27 (s, 3H), 1.49 – 1.39 (m, 3H). LRMS (ESI) m/z: calcd for C ₅₅ H ₆₄ FN ₁₀ O ₆ S ⁺ [M + H] ⁺ , 1011.47; found, 1011.43. Example 12 Synthesis of NS131-11 14-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1-yl)-N- ((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl)-3,6,9,12 -tetraoxatetradecan- 1-amine (NS131-11). NS131-11 was synthesized following the standard for preparing NS131-8 from Intermediate 1 and 14-azido-3,6,9,12-tetraoxatetradecan-1-amine. (white solid, 5.6 mg, 48%) ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.11 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.18 – 8.13 (m, 2H), 8.04 – 7.98 (m, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 8.2, 1.3 Hz, 1H), 7.70 – 7.67 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 1.7 Hz, 1H), 7.53 (dd, J = 8.5, 1.5 Hz, 1H), 7.13 – 7.05 (m, 2H), 6.95 (dt, J = 8.6, 1.6 Hz, 1H), 5.11 (s, 2H), 4.68 (t, J = 7.2 Hz, 2H), 4.56 – 4.38 (m, 6H), 3.89 – 3.74 (m, 7H), 3.66 (tq, J = 5.5, 3.8, 2.8 Hz, 4H), 3.62 – 3.57 (m, 2H), 3.55 – 3.51 (m, 2H), 3.48 (d, J = 11.9 Hz, 5H), 3.31 – 3.27 (m, 4H), 3.19 (q, J = 7.6 Hz, 4H), 3.07 (s, 4H), 2.43 (s, 3H), 2.27 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C ₅₇ H ₆₈ FN ₁₀ O ₇ S ⁺ [M + H] ⁺ , 1055.50; found, 1055.54. Example 13 Synthesis of NS131-12 17-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1-yl)-N- ((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl)-3,6,9,12 ,15- pentaoxaheptadecan-1-amine (NS131-12). NS131-12 was synthesized following the standard for preparing NS131-8 from Intermediate 1 and 17-azido-3,6,9,12,15- pentaoxaheptadecan-1-amine. (white solid, 6.1 mg, 50%) ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.11 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.17 (d, J = 7.9 Hz, 2H), 8.05 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 8.1, 1.4 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4, 1.7 Hz, 1H), 7.53 (dd, J = 8.5, 1.5 Hz, 1H), 7.11 (t, J = 8.5 Hz, 1H), 7.07 (dd, J = 12.0, 2.1 Hz, 1H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 5.13 (s, 2H), 4.67 (t, J = 7.2 Hz, 2H), 4.57 – 4.38 (m, 6H), 3.80 (dt, J = 11.3, 5.3 Hz, 6H), 3.74 – 3.53 (m, 8H), 3.52 – 3.42 (m, 8H), 3.31 (d, J = 1.6 Hz, 6H), 3.19 (t, J = 7.7 Hz, 4H), 3.04 (s, 4H), 2.43 (s, 3H), 2.27 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C59H72FN10O8S ⁺ [M + H] ⁺ , 1099.52; found, 1099.50. Example 14 Synthesis of NS136-37 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihyd roquinolin-1(2H)- yl)-1-(1-(((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl )glycyl)piperidin-4-yl)- N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-car boxamide (NS136- 37). NS136-37 was synthesized following the standard procedure C. To a solution of tert-butyl glycinate (6.5 mg, 0.05 mmol, 1 equiv) in methanol (1 mL) were added Intermediate 1 (15.3 mg, 0.05 mmol, 1.0 equiv), 5 drops AcOH, sodium cyanoborohydride (6.3 mg, 0.1 mmol, 2 equiv). After being stirred 1 h at rt, the resulting mixture was purified by preparative HPLC (10%-100% acetonitrile/ 0.1% TFA in H ₂ O), the solution was evaporated under the reduced pressure to give product as a yellow oil (8.4 mg, 46%). Then the residue was added DCM (1 mL) and TFA (1 mL), stirred at rt for 1h. The mixture was evaporated under the reduced pressure. Then to a solution of last step product (3.65 mg, 0.01 mmol, 1 equiv) in DMF (1 mL) were added Intermediate 3 (5.2 mg, 0.01 mmol, 1.0 equiv), HOAt (1-hydroxy-7-azabenzo-triazole) (2.7 mg, 0.02 mmol, 2 equiv), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (3.8 mg, 0.02 mmol, 2 equiv), and NMM (N-methylmorpholine) (5 mg, 0.05 mmol, 5 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC (10%-100% acetonitrile/ 0.1% TFA in H ₂ O), dried by lyophilization to afford the final compound NS136-37 (white solid, 5.5 mg, 45%). ¹ H NMR (600 MHz, Methanol-d4) δ 9.12 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.5 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.17 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.2, 1.4 Hz, 1H), 7.67 – 7.58 (m, 3H), 7.49 (s, 1H), 7.09 (s, 1H), 6.74 (s, 1H), 6.57 (s, 3H), 4.64 (d, J = 13.6 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.46 – 4.36 (m, 3H), 4.21 – 4.10 (m, 3H), 4.08 (s, 1H), 3.92 (s, 3H), 3.85 (d, J = 13.9 Hz, 1H), 3.70 (dq, J = 33.9, 5.7, 5.3 Hz, 4H), 3.00 – 2.78 (m, 6H), 2.68 (s, 3H), 2.15 – 1.98 (m, 6H), 1.44 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C ₄₇ H ₅₂ F ₂ N ₁₁ O ₂ S ⁺ [M + H] ⁺ , 872.40; found, 872.42. Example 15 Synthesis of NS136-38 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihyd roquinolin-1(2H)- yl)-1-(1-(3-(((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3- yl)methyl)amino)propanoyl)piperidin-4-yl)-N-methyl-1,4,6,7-t etrahydro-5H- pyrazolo[4,3-c]pyridine-5-carboxamide (NS136-38). NS136-38 was synthesized following the standard for preparing NS136-37 from Intermediate 1, 3 and tert-butyl 3- aminopropanoate. (white solid, 4.8 mg, 39%) ¹ H NMR (600 MHz, Methanol-d4) δ 9.13 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.19 – 8.15 (m, 2H), 8.01 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 8.1, 1.5 Hz, 1H), 7.65 – 7.57 (m, 3H), 7.48 (s, 1H), 7.06 (s, 1H), 6.70 (s, 1H), 6.56 (t, J = 55.5 Hz, 3H), 4.66 (d, J = 13.4 Hz, 1H), 4.53 (q, J = 7.2 Hz, 2H), 4.44 (s, 2H), 4.41 – 4.36 (m, 1H), 4.07 (s, 2H), 4.00 (d, J = 14.1 Hz, 1H), 3.92 (s, 3H), 3.72 (t, J = 5.9 Hz, 2H), 3.62 (t, J = 5.7 Hz, 2H), 3.35 (dt, J = 14.2, 7.2 Hz, 3H), 3.27 (s, 1H), 2.84 (dt, J = 26.0, 5.3 Hz, 6H), 2.68 (s, 3H), 2.12 – 1.96 (m, 6H), 1.45 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C ₄₈ H ₅₄ F ₂ N ₁₁ O ₂ S ⁺ [M + H] ⁺ , 886.41; found, 886.38. Example 16 Synthesis of NS136-44 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihyd roquinolin-1(2H)- yl)-1-(1-(3-(2-(2-(((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3- yl)methyl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)-N-me thyl-1,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (NS136-44). NS136-44 was synthesized following the standard for preparing NS136-37 from Intermediate 1, 3 and tert-butyl 3-(2-(2-aminoethoxy)ethoxy)propanoate. (white solid, 4.7 mg, 36%) ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.12 (d, J = 1.9 Hz, 1H), 8.23 (d, J = 1.7 Hz, 1H), 8.18 – 8.13 (m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.1, 1.4 Hz, 1H), 7.63 – 7.53 (m, 3H), 7.47 (s, 1H), 7.04 (s, 1H), 6.71 (s, 1H), 6.56 (t, J = 55.4 Hz, 3H), 4.50 (q, J = 7.1 Hz, 3H), 4.40 (s, 2H), 4.22 – 4.15 (m, 1H), 4.05 (d, J = 1.8 Hz, 2H), 4.01 – 3.95 (m, 1H), 3.90 (s, 3H), 3.77 (q, J = 6.7, 6.2 Hz, 4H), 3.72 – 3.62 (m, 5H), 3.58 (t, J = 5.7 Hz, 2H), 3.26 (q, J = 4.5 Hz, 2H), 3.08 (t, J = 13.0 Hz, 1H), 2.83 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 2.69 (s, 3H), 2.64 – 2.52 (m, 2H), 2.03 – 1.92 (m, 3H), 1.86 – 1.72 (m, 3H), 1.42 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C52H62F ₂ N ₁₁ O ₄ S ⁺ [M + H] ⁺ , 974.47; found, 974.43. Example 17 Synthesis of NS136-45 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihyd roquinolin-1(2H)- yl)-1-(1-(1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-5,8, 11-trioxa-2- azatetradecan-14-oyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrah ydro-5H- pyrazolo[4,3-c]pyridine-5-carboxamide (NS136-45). NS136-45 was synthesized following the standard for preparing NS136-37 from Intermediate 1, 3 and tert-butyl 3- (2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate. (white solid, 5.2 mg, 38%) ¹ H NMR (600 MHz, Methanol-d ₄ ) δ 9.12 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H), 8.17 (dd, J = 4.8, 3.3 Hz, 2H), 8.00 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.2, 1.3 Hz, 1H), 7.65 – 7.55 (m, 3H), 7.48 (s, 1H), 7.05 (s, 1H), 6.71 (s, 1H), 6.56 (t, J = 55.5 Hz, 3H), 4.56 (d, J = 13.6 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.42 (d, J = 8.1 Hz, 3H), 4.24 (dt, J = 10.8, 5.8 Hz, 1H), 4.06 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H), 3.80 – 3.76 (m, 2H), 3.72 – 3.53 (m, 13H), 3.30 – 3.26 (m, 2H), 3.08 (t, J = 13.1 Hz, 1H), 2.84 (t, J = 6.5 Hz, 2H), 2.75 (t, J = 5.8 Hz, 2H), 2.69 (s, 3H), 2.64 – 2.57 (m, 1H), 2.50 – 2.43 (m, 1H), 2.03 – 1.82 (m, 6H), 1.43 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C54H66F ₂ N ₁₁ O5S ⁺ [M + H] ⁺ , 1018.49; found, 1018.45. Example 18 Synthesis of NS136-46 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihyd roquinolin-1(2H)- yl)-1-(1-(1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-5,8, 11,14-tetraoxa-2- azaheptadecan-17-oyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrah ydro-5H- pyrazolo[4,3-c]pyridine-5-carboxamide (NS136-46). NS136-46 was synthesized following the standard for preparing NS136-37 from Intermediate 1, 3 and tert-butyl 1- amino-3,6,9,12-tetraoxapentadecan-15-oate. (white solid, 5.8 mg, 41%) ¹ H NMR (600 MHz, Methanol-d4) δ 9.12 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.17 (dd, J = 4.8, 3.3 Hz, 2H), 8.00 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 8.3, 1.3 Hz, 1H), 7.65 – 7.56 (m, 3H), 7.48 (s, 1H), 7.05 (s, 1H), 6.72 (s, 1H), 6.56 (t, J = 55.4 Hz, 4H), 4.57 (d, J = 13.6 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.44 (s, 2H), 4.26 (dt, J = 11.0, 5.7 Hz, 1H), 4.06 (s, 2H), 3.98 (d, J = 13.7 Hz, 1H), 3.91 (s, 3H), 3.80 (t, J = 5.1 Hz, 2H), 3.71 – 3.47 (m, 17H), 3.29 (d, J = 5.0 Hz, 2H), 3.12 (t, J = 13.1 Hz, 1H), 2.84 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 5.9 Hz, 2H), 2.69 (s, 3H), 2.65 – 2.60 (m, 1H), 2.53 – 2.48 (m, 1H), 2.04 – 1.87 (m, 6H), 1.44 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C ₅₆ H ₇₀ F ₂ N ₁₁ O ₆ S ⁺ [M + H] ⁺ , 1062.52; found, 1062.54. Example 19 Synthesis of NS136-47 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihyd roquinolin-1(2H)- yl)-1-(1-(1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-5,8, 11,14,17-pentaoxa-2- azaicosan-20-oyl)piperidin-4-yl)-N-methyl-1,4,6,7-tetrahydro -5H-pyrazolo[4,3- c]pyridine-5-carboxamide (NS136-47). NS136-47 was synthesized following the standard for preparing NS136-37 from Intermediate 1, 3 and tert-butyl 1-amino- 3,6,9,12,15-pentaoxaoctadecan-18-oate. (white solid, 6.2 mg, 43%) ¹ H NMR (600 MHz, Methanol-d4) δ 9.12 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.17 (dd, J = 4.7, 3.3 Hz, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.2, 1.3 Hz, 1H), 7.65 – 7.56 (m, 3H), 7.48 (s, 1H), 7.05 (s, 1H), 6.72 (s, 1H), 6.57 (t, J = 55.5 Hz, 3H), 4.59 (d, J = 13.5 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.45 (s, 2H), 4.27 (dt, J = 11.1, 5.8 Hz, 1H), 4.06 (s, 2H), 3.99 (d, J = 15.3 Hz, 1H), 3.91 (s, 3H), 3.83 – 3.77 (m, 2H), 3.73 – 3.44 (m, 17H), 3.30 (s, 6H), 3.13 (t, J = 12.7 Hz, 1H), 2.84 (t, J = 6.5 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 2.69 (s, 3H), 2.66 – 2.60 (m, 1H), 2.52 – 2.46 (m, 1H), 2.07 – 1.83 (m, 6H), 1.44 (t, J = 7.2 Hz, 3H).LRMS (ESI) m/z: calcd for C ₅₈ H ₇₄ F ₂ N ₁₁ O ₇ S ⁺ [M + H] ⁺ , 1106.55; found, 1106.52.

Chemistry General Procedures for the Following Examples. All commercial chemical reagents and solvents were used for the reactions without further purification. Flash column chromatography was performed on Teledyne ISCO CombiFlash Rf+ instrument equipped with a 220/254/280 nm wavelength UV detector and a fraction collector. Normal phase column chromatography was conducted on silica gel columns with either hexane/ethyl acetate or dichloromethane/methanol as eluent. Reverse phase column chromatography was conducted on HP C18 RediSep Rf columns, and the gradient was set to 10% of acetonitrile in H ₂ O containing 0.1% TFA progressing to 100% of acetonitrile.. All final compounds were purified with preparative high-performance liquid chromatography (HPLC) on an Agilent Prep 1200 series with the UV detector set to 220/254 nm at a flow rate of 40 mL/min. Samples were injected onto a Phenomenex Luna 750 x 30 mm, 5 μM C18 column, and the gradient was set to 10% of acetonitrile in H ₂ O containing 0.1% TFA progressing to 100% of acetonitrile. All compounds assessed for biological activity have purity > 95% as determined by an Agilent 1200 series system with DAD detector and a 2.1 mm x 150 mm Zorbax 300SB-C18 5 μM column for chromatography and high-resolution mass spectra (HRMS) that were acquired in positive ion mode using an Agilent G1969A API- TOF with an electrospray ionization (ESI) source. Samples (2 μL) were injected onto a C18 column at room temperature, and the flow rate was set to 0.4 mL/min with water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B. Nuclear magnetic resonance (NMR) spectra were acquired on Bruker DRX 600 MHz and 400 MHz for proton ( ¹ H NMR) and 101 MHz for carbon ( ¹³ C NMR). Chemical shifts for all compounds are reported in parts per million (ppm, ?). The format of chemical shift was reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (J values in Hz), and integration. All final compounds had > 95% purity using the HPLC methods described above.

Scheme S1. General synthetic route for preparing compound 1-4a b -- PK9323 n= 1 - -4 ^a Reaction and conditions: (a) HOAt, EDCI , NM::rvl, D MF, rt, 12 h; (b) 10, CuSO.i·5H ₂ O , sodium ascorbate, DMF/IfaO , rt, 2 h. PK9323, 10, 11 and 12 were prepared following previous reported procedures ^{2, 3} . 3-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin oethyl)-lH- benzo[d]imidazol-2- yl)ethyl)-2-fluorophenoxy)methyl)-lH-1,2,3-triazol-1- yl)ethoxy)-N-( (9-ethyl-7-( thiazol-4-yl)-9H-carbazol-3-yl)methyl)-N- methylpropanamide (Compound 1) To a solution of Compound PK9323 (prepared following previous reported procedures) ² (16 mg, 0.05 mmol, 1 equiv) in D.MF (I mL) were added 3-(2- azidoethoxy)propanoic acid (8 mg, 0.05 mmol, 1.0 equiv), HOAt (1-hydroxy-7- azabenzo-triazole) (14 mg, 0.1 mmol, 2 equiv), EDCI (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide) (19 mg, 0.1 mmol, 2 equiv), and NMlv1 (N-methylmorpholine) (25 mg, 0.25 mmol, 5 equiv). After being stirred overnight at room temperature, the resulting mixture was purified by preparative HPLC to afford the desired intermediate as a colorless oil (14 mg, 61% yield). To a solution of compound 10 (prepared following previous reported procedures) ³ (6 mg, 0.012 mmol, 1.0 equiv.) in DMF/H ₂ ( 2:1, 0.9 mL) were added last step intermediate (6 mg, 0.012 mmol, 1.0 equiv.), CuSO ₄ ·5H ₂ O (3 mg, 0.012 mmol, 1.0 equiv.), sodium ascorbate (2 mg, 0.012 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 12 h followed by purified by preparative HPLC to afford compound 1 as a white solid (6 mg, 42% yield). ¹ H NMR (600 MHz, CD ₃ OD) o 9.08 (d, J= 1.9 Hz, l H), 8.10- 8.03 (m, 2H), 8.00- 7.86 (m, 4H), 7.76-7.71 (m, l H), 7.67 (dd, J= 9.0, 1.5 Hz, IH), 7.52 (td, J= 8.5, 1.5 Hz, IH), 7.49-7.45 (m, IH), 7.35-7.30 (m, IH) , 7.03 - 6.95 (m, 2H), 6.86-6.81 (m, 1H), 5.01 (d, J = 11.7 Hz, 2H), 4.75 (d, J = 8.0 Hz, 2H), 4.66-4.61 (m, 2H), 4.58 – 4.54 (m, 2H), 4.46-4.43 (m, 2H), 3.90 – 3.87 (m, 1H), 3.86 – 3.76 (m, 6H), 3.43-3.38 (m, 2H), 3.30 – 3.15 (m, 4H), 3.14 – 3.03 (m, 5H), 2.97 (s, 3H), 2.76-2.71 (m, 2H), 2.42 (d, J = 1.4 Hz, 3H), 2.26 (d, J = 1.1 Hz, 3H), 1.44-1.38 (m, 3H). HRMS (ESI) m/z: calcd for C53H58FN10O5S ⁺ [M + H] ⁺ , 965.4291; found, 965.4288. 3-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpho linoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3 -yl)methyl)-N- methylpropanamide (Compound 2). Compound 2 was synthesized following the standard procedure for preparing compound 1 from PK9323 and 3-(2- (2-azidoethoxy)ethoxy)propanoic acid. (white solid, 5 mg, 39% yield) ¹ H NMR (600 MHz, CD ₃ OD) δ 9.08 (d, J = 2.0 Hz, 1H), 8.14 – 8.06 (m, 2H), 8.04 – 7.87 (m, 4H), 7.76-7.72 (m, 1H), 7.69 – 7.65 (m, 1H), 7.55 – 7.51 (m, 1H), 7.50 – 7.43 (m, 1H), 7.38-7.34 (m, 1H), 7.09 – 7.03 (m, 1H), 7.02 – 6.97 (m, 1H), 6.91 – 6.83 (m, 1H), 5.09-5.04 (m, 2H), 4.77-4.73 (m, 2H), 4.71 – 4.64 (m, 2H), 4.48-4.45 (m, 4H), 3.86 – 3.74 (m, 6H), 3.59 – 3.53 (m, 3H), 3.44-3.41 (m, 2H), 3.28 –3.22 (m, 2H), 3.15 – 3.10 (m, 4H), 2.99-2.96 (m, 3H), 2.79 – 2.68 (m, 2H), 2.66 (s, 5H), 2.42 (d, J = 5.6 Hz, 3H), 2.26 (d, J = 4.5 Hz, 3H), 1.41 (dt, J = 9.0, 7.2 Hz, 3H). HRMS (ESI) m/z: calcd for C ₅₅ H ₆₂ FN ₁₀ O ₆ S ⁺ [M + H] ⁺ , 1009.4553; found, 1009.4551. 2-(2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-mor pholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-car bazol-3-yl)methyl)- N- methylacetamide (Compound 3). Compound 3 was synthesized following the standard for preparing compound 1 from PK9323 and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)acetic acid. (white solid, 6 mg, 43% yield) ¹ H NMR (600 MHz, CD ₃ OD) δ 9.09 (dd, J = 5.0, 1.9 Hz, 1H), 8.11 – 7.83 (m, 6H), 7.75 – 7.62 (m, 2H), 7.53 – 7.44 (m, 2H), 7.41 – 7.33 (m, 1H), 7.12-7.08 (m, 1H), 7.03 – 6.97 (m, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.16-5.11 (m, 2H), 4.71 (d, J = 9.5 Hz, 2H), 4.64-4.61 (m, 2H), 4.54 – 4.40 (m, 4H), 4.36-4.33 (m, 2H), 3.82 (t, J = 5.0 Hz, 4H), 3.72 – 3.62 (m, 3H), 3.60 – 3.51 (m, 4H), 3.50 – 3.41 (m, 2H), 3.32 (s, 4H), 3.27 – 3.05 (m, 7H), 2.98-2.94 (m, 3H), 2.40 (d, J = 7.0 Hz, 3H), 2.24 (d, J = 5.8 Hz, 3H), 1.44-1.38 (m, 3H). HRMS (ESI) m/z: calcd for C56H64FN10O ₇ S ⁺ [M + H] ⁺ , 1039.4653; found, 1039.4657 14-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- 1Jenzo(d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-lH-1,2 ,3-triazol-1-yl)-N- ((9-ethyl-7-(thiazol-4-yl)-9H-carlJazol-3-yl)methyl)-N-methy l-3,6,9,12- tetraoxatetradecanamide (Compound 4) Compound 4 was synthesized following the standard for preparing compound 1 from PK9323 and 14-azido-3,6,9,12-tetraoxatetradecainoic acid. (white solid, 6 mg, 45% yield) ¹ H NMR (600 MHz, CD ₃ OD) o 9.09 (dd, J= 4.0, 2.0 Hz, l H), 8.13-7.94 (m, 5H), 7.90-7.85 (m, IH), 7.76-7.63 (m, 2H), 7.54 - 7.44 (m, 2H), 7.41 - 7.34 (m, IH), 7.11 (q, J= 8.3 Hz, l H), 7.09- 7.00 (m, l H), 6.90 (t, J= 9.1 Hz, IH), 5.18-5.13 (m, 2H), 4.73 (d, J= 10.9 Hz, 2H), 4.68-4.63 (m, 2H), 4.55 - 4.41 (m, 4H), 4.39-4.36 (m, 2H), 3.87- 3.74 (m, SH), 3.70-3.56 (m, 4H), 3.55 -3.39 (m, 8H), 3.36 (t, J= 7.7 Hz, 4H), 3.28 - 3.07 (m, 7H), 2.99-2.96 (m, 3H), 2.40 (d, J = 8.3 Hz, 3H), 2.24 (d, J = 7.5 Hz, 3H), 1.46 - 1.37 (m, 3H). HR.MS (ESI) m/z: calcd for Cs8H6sFN10OsS ⁺ [M + H] ⁺ , 1083.4921; found, 1083.4914. Scheme S2. General synthetic route for preparing compound 5-9 ^{? a} Reaction and conditions: (a) CuSO ₄ ·5H ₂ O, sodium ascorbate, DMF/H ₂ 0 , rt, 12 h; (b) 9-ethyl-7-(thiazol-4-yl)-9H-carbazole-3-carbaldehyde (11), Eb N, acetic acid, sodium cyanoborohydride, MeOH, rt, 2 h. 2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin oethyl)-lH- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-l H-1,2,3-triazol-1- yl)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)met hyl)ethan-1-amine (Compound 5). To a solution of compound 10 (40 mg, 0.08 mmol, 1.0 equiv.) in DMF/H ₂ O (2:1, 0.9 mL) were added 2-(2-azidoethoxy)ethan-1-amine (10 mg, 0.08 mmol, 1.0 equiv.), CuSO ₄ .5H ₂ O (20 mg, 0.08 mmol, 1.0 equiv.), sodium ascorbate (16 mg, 0.08 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 12 h followed by purified by preparative HPLC to afford intermediate as a colorless oil (26 mg, 52% yield). To a solution of intermediate (8 mg, 0.01 mmol, 1.0 equiv.) in methanol (1 mL) were added compound 11 (prepared following previous reported procedures) ² (3 mg, 0.01 mmol, 1.0 equiv.), 3 drops Et3N, then 5 drops AcOH. After the reaction solution was stirred at rt for 1h, sodium cyanoborohydride (3 mg, 0.05 mmol, 5.0 equiv.) was added and continued being stirred for 2 h at room temperature. Then, the resulting mixture was purified by preparative HPLC to give the titled compound 5 as white solid (4 mg, 41% yield). ¹ H NMR (600 MHz, CD ₃ OD) δ 9.12 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.17 (dd, J = 4.7, 3.3 Hz, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.2, 1.3 Hz, 1H), 7.65 – 7.56 (m, 3H), 7.48 (s, 1H), 7.05 (s, 1H), 6.72 (s, 1H), 6.57 (t, J = 55.5 Hz, 3H), 4.59 (d, J = 13.5 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.45 (s, 2H), 4.27 (dt, J = 11.1, 5.8 Hz, 1H), 4.06 (s, 2H), 3.99 (d, J = 15.3 Hz, 1H), 3.91 (s, 3H), 3.83 – 3.77 (m, 2H), 3.73 – 3.44 (m, 17H), 3.30 (s, 6H), 3.13 (t, J = 12.7 Hz, 1H), 2.84 (t, J = 6.5 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 2.69 (s, 3H), 2.66 – 2.60 (m, 1H), 2.52 – 2.46 (m, 1H), 2.07 – 1.83 (m, 6H), 1.44 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C51H56FN10O ₄ S ⁺ [M + H] ⁺ , 923.4185; found, 923.4177. 2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpho linoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3 -yl)methyl)ethan-1- amine (Compound 6). Compound 6 was synthesized following the standard for preparing compound 5 from 10 and 2-(2-(2-azidoethoxy)ethoxy)ethan- 1-amine. (white solid, 4 mg, 39% yield) ¹ H NMR (600 MHz, CD ₃ OD) δ 9.09 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 1.7 Hz, 1H), 8.15 (dd, J = 4.7, 3.3 Hz, 2H), 8.05 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.84 – 7.81 (m, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.55 (ddd, J = 8.6, 4.3, 1.6 Hz, 2H), 7.06 – 7.01 (m, 2H), 6.91 (dt, J = 8.3, 1.5 Hz, 1H), 5.05 (s, 2H), 4.75 (t, J = 7.5 Hz, 2H), 4.57 (t, J = 5.0 Hz, 2H), 4.50 (q, J = 7.2 Hz, 2H), 4.39 (s, 2H), 3.92 (t, J = 5.0 Hz, 2H), 3.86 (t, J = 4.7 Hz, 4H), 3.71 – 3.61 (m, 6H), 3.45 (t, J = 7.8 Hz, 2H), 3.34 (s, 2H), 3.25 – 3.09 (m, 8H), 2.43 (s, 3H), 2.27 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C ₅₃ H ₆₀ FN ₁₀ O ₅ S ⁺ [M + H] ⁺ , 967.4447; found, 967.4445. 2-(2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-mor pholinoethyl)-1H- benzo[d] 60 midazole-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2,3-triazo l-1- yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(thiazol-4-yl)-9H-car bazol-3- yl)methyl)ethan-1- amine (Compound 7). Compound 7 was synthesized following the standard for preparing compound 5 from 10 and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-amine. (white solid, 6 mg, 51% yield) ¹ H NMR (600 MHz, CD ₃ OD) δ 9.10 (q, J = 2.0 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.15 (q, J = 3.6 Hz, 2H), 8.02 – 7.95 (m, 2H), 7.93 (dd, J = 8.5, 3.2 Hz, 1H), 7.82 (dd, J = 8.7, 3.1 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.62 – 7.51 (m, 3H), 7.07 (ddt, J = 10.9, 7.3, 4.1 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 5.07 (d, J = 3.1 Hz, 2H), 4.71 (d, J = 7.1 Hz, 2H), 4.56 – 4.36 (m, 6H), 3.88 – 3.73 (m, 7H), 3.66 – 3.43 (m, 11H), 3.29 – 2.98 (m, 10H), 2.43 (s, 3H), 2.27 (s, 3H), 1.49 – 1.39 (m, 3H). LRMS (ESI) m/z: calcd for C ₅₅ H ₆₄ FN ₁₀ O ₆ S ⁺ [M + H] ⁺ , 1011.4710; found, 1011.4706. 14-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1-yl)-N- ((9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)methyl)-3,6,9,12 -tetraoxatetradecan- 1-amine (Compound 8). Compound 8 was synthesized following the standard for preparing compound 5 from 10 and 14-azido-3,6,9,12- tetraoxatetradecan-1-amine. (white solid, 6 mg, 48% yield) ¹ H NMR (600 MHz, CD ₃ OD) δ 9.11 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.18 – 8.13 (m, 2H), 8.04 – 7.98 (m, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 8.2, 1.3 Hz, 1H), 7.70 – 7.67 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 1.7 Hz, 1H), 7.53 (dd, J = 8.5, 1.5 Hz, 1H), 7.13 – 7.05 (m, 2H), 6.95 (dt, J = 8.6, 1.6 Hz, 1H), 5.11 (s, 2H), 4.68 (t, J = 7.2 Hz, 2H), 4.56 – 4.38 (m, 6H), 3.89 – 3.74 (m, 7H), 3.66 (tq, J = 5.5, 3.8, 2.8 Hz, 4H), 3.62 – 3.57 (m, 2H), 3.55 – 3.51 (m, 2H), 3.48 (d, J = 11.9 Hz, 5H), 3.31 – 3.27 (m, 4H), 3.19 (q, J = 7.6 Hz, 4H), 3.07 (s, 4H), 2.43 (s, 3H), 2.27 (s, 3H), 1.44 (t, J =7.2 Hz, 3H). LRMS (ESI) m/z: calcd for C57H68FN10O ₇ S ⁺ [M + H] ⁺ , 1055.4972; found, 1055.4975. 17-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholinoe thyl)-1H- benzofd] 61 arbazole-2- yl)ethyl)-2-fluorophenoxy)methyl)-lH-1,2,3-triazol-1-yl)- N-((9-ethyl-7-(thiazol-4-yl)-9H- 61 arbazole-3-yl)methyl)-3,6,9,12,15- pentaoxaheptadecan-1-amine (Compound 9). Compound 9 was synthesized following the standard for preparing compound 5 from 10 and I 7-azido-3,6,9,12,15- pentaoxaheptadecan-1-amine. (white solid, 6 mg, 50% yield) ]H NMR (600 MHz, CD ₃ OD) 89.11 (d, J= 1.9 Hz, IH), 8.26 (d, J= 1.7 Hz, l H), 8.17 (d, J= 7.9 Hz, 2H), 8.05 (s, l H), 8.00 (d, J=2.0 Hz, l H), 7.91 (d, J= 8.5 Hz, l H), 7.83 (dd, J= 8.1, 1.4 Hz, l H), 7.68 (d, J= 1.5 Hz, l H), 7.63 (d, J = 8.4 Hz, l H), 7.58 (dd, J= 8.4, 1.7 Hz, l H), 7.53 (dd, J= 8.5, 1.5 Hz, l H), 7.11 (t, J= 8.5 Hz, l H), 7.07 (dd, J= 12.0, 2.1 Hz, l H), 6.95 (dd, J= 8.0, 2.0 Hz, l H), 5.13 (s, 2H), 4.67 (t, J=7.2 Hz, 2H), 4.57 - 4.38 (m, 6H), 3.80 (dt, J= 11.3, 5.3 Hz, 6H), 3.74 - 3.53 (m, 8H), 3.52 - 3.42 (m, 8H), 3.31 (d , J = 1.6 Hz, 6H), 3.19 (t , J = 7.7 Hz, 4H), 3.04 (s, 4H), 2.43 (s, 3H), 2.27 (s, 3H), 1.44 (t, J= 7.2 Hz, 3H). HRMS (Esn m/z: calcd for Cs9H12FN10OsS+ [M + H]+, 1099.5234; found, 1099.5238. Scheme S3. General synthetic route for preparing Compound 13 (MS78)a a Reaction and conditions: (a) EhN, acetic acid, sodium cyanoborohydride, MeOH, rt, 12 h; (b) 10, CuSO ₄ -5H ₂ O, sodium ascorbate, DMF/H ₂ O, 50 °C, 2 h. 2-(2-(2-(2-(4-((4-(2-(5-(3,5-dimethylisoxazol-4-yl)-1-(2-mor pholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)-2-fluorophenoxy)methyl)-1H-1,2, 3-triazol-1- yl)ethoxy)ethoxy)ethoxy)-N-((9-ethyl-7-(4-methylthiophen-2-y l)-9H-carbazol-3- yl)methyl)ethan-1-amine (Compound 13, MS78). To a solution of compound 12 (28 mg, 0.09 mmol, 1.0 equiv. prepared following previously published procedures ² ) in methanol (1 mL) were added 2-(2-(2-(2-azidoethoxy)e thoxy)ethoxy)ethan-1-amine (20 mg, 0.01 mmol, 1.0 equiv.), 3 drops EtJN, then 5 drops AcOH and the reaction solution was stirred at rt for lh. Then, sodium cyanoborohydride (17 mg, 0.27 mmol, 3.0 equiv.) was added followed by stirred for additional 12 h at room temperature. The resulting mixture was purified by preparative HPLC to give the desired intermediate as a yellow oil (19 mg, 39% yield). To a solution of last step desired intermediate (15 mg, 0.029 mmol, 1.0 equiv.) in DMF/H ₂ O (2:1, 1.2 mL) were added compound 10 (15 mg, 0.029 mmol, 1.0 equiv.), CuSO ₄ 5H ₂ O (7 mg, 0.019 mmol, 1.0 equiv.), sodium ascorbate (6 mg, 0.019 mmol, 1.0 equiv.). The resulting mixture was stirred at 50 oC for 2 h followed by purified by preparative HPLC to afford the compound 13 (MS78) as a yellow solid (10 mg, 24% yield).1H NMR (400 MHz, CD ₃ OD) δ 8.19 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.67 (s, 1H), 7.57 – 7.45 (m, 4H), 7.32 (s, 1H), 7.05 - 7.03 (m, 2H), 6.91 -6.90 (m, 2H), 5.04 (s, 2H), 4.65 (s, 2H), 4.44 – 4.40 (m, 6H), 3.80 – 3.74 (m, 8H), 3.62 - 3.55 (m, 8H), 3.42 (s, 2H), 3.30 - 3.26 (m, 2H), 3.19 – 3.17 (m, 4H), 3.06 (s, 4H), 2.42 (s, 3H), 2.26 (s, 6H), 1.39 (s, 3H). ¹³ C NMR (101 MHz, CD ₃ OD) δ 167.44, 159.92, 156.01, 155.21, 152.76, 146.46 (d, 3JC-F = 9.0 Hz), 145.92, 144.26, 142.30, 142.29, 140.04, 135.81, 134.52, 134.44, 133.27, 128.61, 126.78, 126.66 (d, ¹ JC-F = 236.0 Hz), 126.18, 125.52, 124.44, 123.34, 123.01, 122.73, 121.83, 121.26, 118.77, 117.28 (d, ² JC-F = 34.0 Hz), 117.27, 117.19, 117.18, 117.11, 113.41, 110.46, 106.70, 71.43, 71.35, 71.27, 71.26, 70.22, 66.80, 66.00, 63.57, 55.88, 54.06, 52.72, 51.33, 47.69, 41.05, 38.51, 32.91, 28.87, 15.85, 14.06, 11.41, 10.65. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C57H67FN9O6S, 1024.4914; found, 1024.4931. Certain compounds disclosed herein have the structures shown in Tables 1 and 2. Table 1. List of the compounds that have already been synthesized. A compound ID is provided in addition to an example number for each compound. Compounds 1 – 9 and 13 (MS78) have been synthesized but are not listed in Table 1 Ex- Compound Compound Structure Compound Name mple ID 3-(2-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2- yl)ethyl)-2- NS125-033 fluorophenoxy)methyl)-1H- 1,2,3-triazol-1-yl)ethoxy)- N-((9-ethyl-7-(thiazol-4-yl)- 9H-carbazol-3-yl)methyl)- N-methylpropanamide 3-(2-(2-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- S N morpholinoethyl)-1H- N N O O N N O benzo[d]imidazol-2- N NS125-034 O yl)ethyl)-2- F N O N N N fluorophenoxy)methyl)-1H- O 1,2,3-triazol-1- yl)ethoxy)ethoxy)-N-((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)methyl)-N- methylpropanamide 2-(2-(2-(2-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2- yl)ethyl)-2- NS125-035 fluorophenoxy)methyl)-1H- 1,2,3-triazol-1- yl)ethoxy)ethoxy)ethoxy)- N-((9-ethyl-7-(thiazol-4-yl)- 9H-carbazol-3-yl)methyl)- N-methylacetamide 14-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2- yl)ethyl)-2- NS125-036 fluorophenoxy)methyl)-1H- 1,2,3-triazol-1-yl)-N-((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)methyl)-N- methyl-3,6,9,12- tetraoxatetradecanamide 5-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2- yl)ethyl)-2- NS125-037 fluorophenoxy)methyl)-1H- 1,2,3-triazol-1-yl)-N-((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)methyl)-N- methylpentanamide 2-(2-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- S N N benzo[d]imidazol-2- H N N N O N yl)ethyl)-2- NS131-8 O F N O fluorophenoxy)methyl)-1H- N N N 1,2,3-triazol-1-yl)ethoxy)- O N-((9-ethyl-7-(thiazol-4-yl)- 9H-carbazol-3- yl)methyl)ethan-1-amine 0 2-(2-(2-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- NS131-9 benzo[d]imidazol-2- yl)ethyl)-2- fluorophenoxy)methyl)-1H- 1,2,3-triazol-1- yl)ethoxy)ethoxy)-N-((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)methyl)ethan- 1-amine 1 2-(2-(2-(2-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2- yl)ethyl)-2- NS131-10 fluorophenoxy)methyl)-1H- 1,2,3-triazol-1- yl)ethoxy)ethoxy)ethoxy)- N-((9-ethyl-7-(thiazol-4-yl)- 9H-carbazol-3- yl)methyl)ethan-1-amine 2 14-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2- yl)ethyl)-2- NS131-11 fluorophenoxy)methyl)-1H- 1,2,3-triazol-1-yl)-N-((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)methyl)- 3,6,9,12-tetraoxatetradecan- 1-amine 3 17-(4-((4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2- yl)ethyl)-2- fluorophenoxy)methyl)-1H- NS131-12 1,2,3-triazol-1-yl)-N-((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)methyl)- 3,6,9,12,15- pentaoxaheptadecan-1- amine 4 3-(7-(difluoromethyl)-6-(1- methyl-1H-pyrazol-4-yl)- 3,4-dihydroquinolin-1(2H)- yl)-1-(1-(((9-ethyl-7- (thiazol-4-yl)-9H-carbazol- NS136-37 3- yl)methyl)glycyl)piperidin- 4-yl)-N-methyl-1,4,6,7- tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carboxamide 5 3-(7-(difluoromethyl)-6-(1- methyl-1H-pyrazol-4-yl)- 3,4-dihydroquinolin-1(2H)- NS136-38 yl)-1-(1-(3-(((9-ethyl-7- (thiazol-4-yl)-9H-carbazol- 3- yl)methyl)amino)propanoyl) piperidin-4-yl)-N-methyl- 1,4,6,7-tetrahydro-5H- pyrazolo[4,3-c]pyridine-5- carboxamide 6 3-(7-(difluoromethyl)-6-(1- methyl-1H-pyrazol-4-yl)- 3,4-dihydroquinolin-1(2H)- yl)-1-(1-(3-(2-(2-(((9-ethyl- 7-(thiazol-4-yl)-9H- NS136-44 carbazol-3- yl)methyl)amino)ethoxy)eth oxy)propanoyl)piperidin-4- yl)-N-methyl-1,4,6,7- tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carboxamide 7 3-(7-(difluoromethyl)-6-(1- methyl-1H-pyrazol-4-yl)- 3,4-dihydroquinolin-1(2H)- yl)-1-(1-(1-(9-ethyl-7- (thiazol-4-yl)-9H-carbazol- NS136-45 3-yl)-5,8,11-trioxa-2- azatetradecan-14- oyl)piperidin-4-yl)-N- methyl-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine- 5-carboxamide 8 3-(7-(difluoromethyl)-6-(1- methyl-1H-pyrazol-4-yl)- 3,4-dihydroquinolin-1(2H)- yl)-1-(1-(1-(9-ethyl-7- (thiazol-4-yl)-9H-carbazol- NS136-46 3-yl)-5,8,11,14-tetraoxa-2- azaheptadecan-17- oyl)piperidin-4-yl)-N- methyl-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine- 5-carboxamide 9 3-(7-(difluoromethyl)-6-(1- methyl-1H-pyrazol-4-yl)- 3,4-dihydroquinolin-1(2H)- yl)-1-(1-(1-(9-ethyl-7- (thiazol-4-yl)-9H-carbazol- NS136-47 3-yl)-5,8,11,14,17-pentaoxa- 2-azaicosan-20- oyl)piperidin-4-yl)-N- methyl-1,4,6,7-tetrahydro- 5H-pyrazolo[4,3-c]pyridine- 5-carboxamide

Table 2. List of the designed p53Y220C acetylators that can be synthesized according to the schemes set forth above. Example Compound Structure Compound Name 20 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-((((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)methyl)aceta mide ₂₁ 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(2-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)ethyl)acetami de 22 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(3-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)propyl)aceta mide 23 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(4-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)butyl)acetami de 24 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(5-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)pentyl)acetam ide 25 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(6-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)hexyl)acetami de 26 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(7-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)heptyl)acetam ide 27 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(8-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)octyl)acetami de 28 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(9-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)nonyl)acetam ide 29 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(10-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)decyl)acetami de 30 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(11-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)undecyl)aceta mide 31 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(2-(2-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)ethoxy)ethyl) acetamide 32 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(2-(2-(2- (((9-ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)ethoxy)ethox y)ethyl)acetamide 33 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(1-(9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)-5,8,11-trioxa-2- azatridecan-13-yl)acetamide 34 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- S N N morpholinoethyl)-1H- H N O O O _O ^O benzo[d]imidazol-2-yl)ethyl)- N H O 2-fluorophenoxy)-N-(1-(9- F N ethyl-7-(thiazol-4-yl)-9H- N N O O N carbazol-3-yl)-5,8,11,14- tetraoxa-2-azahexadecan-16- yl)acetamide ₃₅ 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(1-(9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)-5,8,11,14,17- pentaoxa-2-azanonadecan-19- yl)acetamide 36 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-2-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)acetamide 37 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-3-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)propanamide ³⁸ _{N-(2-(4-(2-(5-(3,5-} dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-4-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)butanamide 39 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- S N morpholinoethyl)-1H- N H N O N H N benzo[d]imidazol-2-yl)ethyl)- N O O N F 2-fluorophenoxy)ethyl)-5-(((9- N ethyl-7-(thiazol-4-yl)-9H- O carbazol-3- yl)methyl)amino)pentanamide 40 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-6-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)hexanamide 41 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- S N morpholinoethyl)-1H- N H N O N H benzo[d]imidazol-2-yl)ethyl)- N N O O N F 2-fluorophenoxy)ethyl)-7-(((9- N ethyl-7-(thiazol-4-yl)-9H- O carbazol-3- yl)methyl)amino)heptanamide 42 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-8-(((9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)octanamide 43 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- S N morpholinoethyl)-1H- N H N O N H benzo[d]imidazol-2-yl)ethyl)- N N O O N F 2-fluorophenoxy)ethyl)-9-(((9- N O ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)nonanamide 44 N-(2-(4-(2-(5-(3,5- S N dimethylisoxazol-4-yl)-1-(2- N H N morpholinoethyl)-1H- O N O H _O ^F benzo[d]imidazol-2-yl)ethyl)- N N 2-fluorophenoxy)ethyl)-10- N (((9-ethyl-7-(thiazol-4-yl)-9H- O ^N carbazol-3- yl)methyl)amino)decanamide ₄₅ N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-11- (((9-ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)undecanamid e 46 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-12- (((9-ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)dodecanamid e 47 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-3-(2- (((9-ethyl-7-(thiazol-4-yl)-9H- carbazol-3- yl)methyl)amino)ethoxy)propa namide ₄₈ N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-4-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)butanamide 49 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-1-(9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)-5,8,11-trioxa-2- azatetradecan-14-amide 50 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-1-(9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)-5,8,11,14- tetraoxa-2-azaheptadecan-17- amide ₅₁ N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-1-(9- ethyl-7-(thiazol-4-yl)-9H- carbazol-3-yl)-5,8,11,14,17- pentaoxa-2-azaicosan-20- amide 52 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-((((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)methyl)aceta mide 53 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(2-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)ethyl)acetami de 54 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(3-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)propyl)aceta mide 55 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(4-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)butyl)acetami de 56 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(5-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)pentyl)acetam ide 57 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- N S H morpholinoethyl)-1H- N O N benzo[d]imidazol-2-yl)ethyl)- H O 2-fluorophenoxy)-N-(6-(((9- F ethyl-7-(4-methylthiophen-2- N N N O O yl)-9H-carbazol-3- N yl)methyl)amino)hexyl)acetami de 58 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(7-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)heptyl)acetam ide 60 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(8-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)octyl)acetami de 61 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(9-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)nonyl)acetam ide 62 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(10-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)decyl)acetami de 63 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(11-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)undecyl)aceta mide 64 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(2-(2-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)ethoxy)ethyl) acetamide 65 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(2-(2-(2- (((9-ethyl-7-(4- methylthiophen-2-yl)-9H- carbazol-3- yl)methyl)amino)ethoxy)ethox y)ethyl)acetamide 66 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(1-(9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3-yl)-5,8,11- trioxa-2-azatridecan-13- yl)acetamide 67 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(1-(9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3-yl)- 5,8,11,14-tetraoxa-2- azahexadecan-16-yl)acetamide 68 2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)-N-(1-(9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3-yl)- 5,8,11,14,17-pentaoxa-2- azanonadecan-19-yl)acetamide 69 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-2-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)acetamide 70 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-3-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)propanamide 71 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-4-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)butanamide 72 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-5-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)pentanamide 73 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-6-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)hexanamide ₇₄ N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-7-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)heptanamide 75 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-8-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)octanamide 76 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-9-(((9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3- yl)methyl)amino)nonanamide ₇₇ N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-10- (((9-ethyl-7-(4- methylthiophen-2-yl)-9H- carbazol-3- yl)methyl)amino)decanamide 78 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-11- (((9-ethyl-7-(4- methylthiophen-2-yl)-9H- carbazol-3- yl)methyl)amino)undecanamid e 79 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-12- (((9-ethyl-7-(4- methylthiophen-2-yl)-9H- carbazol-3- yl)methyl)amino)dodecanamid e 80 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-3-(2- (((9-ethyl-7-(4- methylthiophen-2-yl)-9H- carbazol-3- yl)methyl)amino)ethoxy)propa namide 81 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-3-(2- (2-(((9-ethyl-7-(4- methylthiophen-2-yl)-9H- carbazol-3- yl)methyl)amino)ethoxy)ethox y)propanamide 82 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-1-(9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3-yl)-5,8,11- trioxa-2-azatetradecan-14- amide 83 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-1-(9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3-yl)- 5,8,11,14-tetraoxa-2- azaheptadecan-17-amide 84 N-(2-(4-(2-(5-(3,5- dimethylisoxazol-4-yl)-1-(2- morpholinoethyl)-1H- benzo[d]imidazol-2-yl)ethyl)- 2-fluorophenoxy)ethyl)-1-(9- ethyl-7-(4-methylthiophen-2- yl)-9H-carbazol-3-yl)- 5,8,11,14,17-pentaoxa-2- azaicosan-20-amide As used herein, in case of discrepancy between the compound structure and compound name provided for a particular compound, the given structure shall control. Example 85. p21 induction of p53Y220C acetylators (Fig.1). NS131-8, NS131-9, NS131-10, NS131-11 and NS131-12 induced the p21 protein level in BxPC3 cells in a concentration-dependent manner. NS125-035 and NS125-036 slightly induced the p21 protein level. Example 86. p53-acetylation of p53Y220C acetylators (Fig.2). Compared with DMSO and the p53Y220C small-molecule binder PK9323, NS131-8, NS131-9, NS131-10, NS131-11 and NS131-12 induced p53-K382 acetylation in an IP assay. Among these compounds, NS131-10 most effectively induced p53-K382 acetylation. Example 87. NS131-10 induces time-dependent p53Y220C acetylation (Fig.3). NS131-10 induced p53-K382 acetylation starting from 2 h and more significant acetylation at 24 h. Example 88. NS131-10 suppresses the growth in p53Y220C mutant cancer cell lines (Fig.4). Cell growth inhibition effect of NS131-10 was tested in serial dilution in two different p53Y220C cancer cell lines (BxPC3 and Huh7). NS131-10 effectively inhibited the growth in both cell lines. Materials and Methods: General Chemistry Methods For the synthesis of intermediates and examples (1-19) below, HPLC spectra for all compounds were acquired using an Agilent 1200 Series system with DAD detector. Chromatography was performed on a 2.1×150 mm Zorbax 300SB-C185 µm column with water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 0.4 ml/min. The gradient program was as follows: 1% B (0δ1 min), 1δ99% B (1δ4 min), and 99% B (4δ8 min). High-resolution mass spectra (HRMS) data were acquired in positive ion mode using an Agilent G1969A API-TOF with an electrospray ionization (ESI) source. Nuclear Magnetic Resonance (NMR) spectra were acquired on a Bruker DRX-600 spectrometer with 600 MHz or 800 MHz for proton ( ¹ H NMR) and 150 MHz for carbon ( ¹³ C NMR); chemical shifts are reported in (δ). Preparative HPLC was performed on Agilent Prep 1200 series with UV detector set to 254 nm. Samples were injected onto a Phenomenex Luna 250 x 30 mm, 5 µm, C18 column at room temperature. The flow rate was 40 ml/min. A linear gradient was used with 10% (or 50%) of MeOH (A) in H ₂ O (with 0.1 % TFA) (B) to 100% of MeOH (A). HPLC was used to establish the purity of target compounds. All final compounds had > 95% purity using the HPLC methods described above. Cell Culture NCI-H1299 and BxPC3 cell lines were cultivated in RPMI-1640 medium while Huh7 cell line was supplemented in DMEM medium with 10% FBS, 100 units/mL of penicillin/streptomycin. NCI-H1299 stable cell line expressing p53Y220C-FLAG was cultivated in RPMI-1640 medium supplemented with 10% FBS, 100 units/mL of penicillin/streptomycin and G418 (500 δg/mL). Cell Viability BxPC3 and Huh7 cells were seeded at 5x10 ⁴ cells/mL density into 96-well microplates (Thermo Scientific) and treated with DMSO or the indicated compounds with serial dilution in triplicates for 4 days. Cell viability was measured using WST-8 reagent (CK04, Dojindo). Briefly, ten microliters of WST-8 reagent was added to each well, and the plates were kept in an incubator at 37 °C for 3 h in the dark. Absorbance signals for WST-8 were read at 450 nm with 650 nm as reference performed with Infinite F PLEX plate reader (TECAN, Morrisville, NC). GI50 values were analyzed using GraphPad Prism 8. Western Blotting Cells were lysed on ice for 30 min with the lysis buffer (50 mM Tris pH 7.4, 1% IGEPAL CA-630, 150 mM NaCl, 1 mM EDTA, and 1 mM AESBF), supplemented with protease and phosphatase inhibitor cocktail (A32961, Thermo Fisher Scientific). The sample was centrifuged at 12000g for 10 min at 4 °C to get supernatant as cell lysate. The primary antibodies used were p53 (Cat#10442-1-AP, Proteintech), p21 (Cat#2947S, Cell Signaling Technology), acetyl-382 lysing p53 (p53382Kac) (Cat#2525L, Cell Signaling Technology), DYKDDDDK (FLAG) Tag (Cat# 14793S, Cell Signaling Technology) and Vinculin (Cat#4650S, Cell Signaling Technology). LI-COR secondary antibodies (IRDye ^? Donkey anti-rabbit IgG) was used to obtain protein signals, which were then analyzed by Image Studio Lite software (LI-COR). Cell Lines, Tissue Culture and Transfection. NCI-H1299 (CRL-5803), BxPC3 (CRL-1687) and U-2OS (HTB-96) were purchased from the American Tissue Culture Collection (ATCC, Manassas, VA). In addition, NUGC-3 were obtained from the Japan Health Science Research Resources Bank (JCRB, JCRB0822). NCI-H1299, BxPC3 and NUGC-3 were cultured in RPMI 1640 medium (Thermo Fisher Scientific Inc., Waltham, Massachusetts) supplemented with 10% heat-inactivated fetal bovine serum Gibco ^TM (FBS) (Life Technologies, Grand Island, NY) and 1% GibcoTM Penicillin/Streptomycin (Life Technologies, Grand Island, NY). U-2OS were cultured in McCoy's 5A (Modified) Medium (Thermo Fisher Scientific Inc., Waltham, Massachusetts) supplemented with 10% heat-inactivated FBS and 1% Penicillin/Streptomycin. All cells were incubated at 37 ?°C in a standard humidified incubator containing 5% CO ₂ and 95% O ₂ . For siRNA transfection, control and p300 siRNA (sc-29431) were purchased from Santa Cruz Biotechnology. Briefly, NCI-H1299 cells were seeded on 6-well plates at a density of 3?δ?10 ⁵ cells/well (~75–80% confluency). Cells were transfected the following day with Lipofectamine 3000 transfection reagent (L3000008, ThermoFisher Scientific) and harvested 48?h after transfection. For the construction of FLAG- p53Y220C stable cell lines, transfected NCI-H1299 cells were selected with G418 for 14 days. Antibodies and Immunoblotting. Total cell lysate was used for western blots, as previously described. ⁴⁷ The following primary antibodies were used in the study: Vinculin (Cell Signaling Technology [CST], 13901), p53 (CST, 2527), acetyl-p53 (lys-382) (CST, 2525), acetyl-p53 (lys-379) (CST, 2570), p21 (CST, 2947), p300 (CST, 86377), p53 polyclonal antibody (Proteintech, 10442-1-AP). Blots were imaged using fluorescence-labeled secondary antibodies on LI-COR Odyssey CLx Imaging Systems. CBP/p300 Binding Assays and Selectivity Against Other Bromodomain-containing Proteins. CBP/p300 bromodomain binding affinities were determined using the AlphaScreen assay (conducted by Reaction Biology Corp.) as described previously. ³⁵ MS78 was prepared as 10 mM stock in 100% DMSO. Kd values were determined by testing MS78 in duplicates against the bromodomain of CBP/p300 in 10-concentration with a 2-fold serial dilution starting at a concentration of 20 ?M. MS78 was further in BromoMelt ^TM profiling assay by Reaction Biology Corp. tested against other bromodomain- containing proteins at 10 µM in duplicates. CETSA The CETSA assays were performed as previously described. ²⁷ Briefly, p53Y220C stable cells were treated with DMSO, PK9328 or MS78 for 1 hour and subsequently harvested by scraping in PBS and pelleted. Cells were resuspended in 500 δL PBS with 1× complete EDTA-free protease inhibitor cocktail (Sigma, #11836170001) and split into 50 δL aliquots in an 8-tube strip (USA Scientific, #1402-4700). The cell suspension was heated with a gradient from 30°C to 50°C in a thermocycler for 3 minutes and then cooled to 25°C for 3 minutes. The heat-treated samples were flash-frozen in liquid nitrogen, thawed at 25°C, and briefly vortexed. The freeze–thaw cycle was repeated three times in total. Samples were cleared of aggregate by centrifugation at 20,000 × g and 4°C for 20 minutes. Cleared supernatant (30 δL) was mixed with 5× SDS-loading buffer for WB analysis. FLAG-immunoprecipitation. Endogenous co-IP experiments were performed as described previously. ⁴⁸ Briefly, 2 ×10 ⁶ cells were seeded in a 10-cm dish, and treated with 0, 1 or 10 μM of MS78 for 24 h. Cells were then washed with ice-cold PBS twice and centrifuged at 200g for 3 min to get cell pellets which were then lysed with 300 δL of lysis buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 2 mM EDTA, 1% Triton X-100, and EDTA-free phosphotase and protease inhibitor) for 30 min on ice, and centrifuged at 14,000g for 10 min to get supernatant as cell lysate. The ANTI-FLAG® M2 affinity gel (Product #A2220, Sigma- Aldrich, Inc.) was used for the purification of FLAG-p53Y220C, according to the manufacturer’s guidelines. Following incubation of M2 affinity gel, protein was eluted using 3X FLAG ^® Peptide (Product #F4799, Sigma-Aldrich, Inc.) and supernatant was resuspended in 30 δL of 1 × SDS-PAGE Laemmli buffer for boiling. The protein samples were then tested by WB. Cell Viability Assay. The cell viability assay was performed as previously described. ⁴⁸ Briefly 5x10 ⁴ cells were seeded per well into 96-well microplates. After 24 h, cells were treated with 3- fold serially diluted compounds in triplicate for 72h. Cell viability was evaluated using WST-8 reagent (CK04, Dojindo). Absorbance signals were obtained with Infinite F PLEX plate reader (TECAN, Morrisville, NC) at 450 nm with 690 nm as reference wavelength after 3 h incubation at 37 ^° C. GraphPad Prism 8 was used in the analysis of GI50 values from the data of three independent experiments. Clonogenic Assay. The clonogenic assay was performed as previously described. ⁴⁸ BxPC3 or NUGC-3 cells (2000 cells per well) were seeded into 12-well tissue culture plates. After 24 h, cells were treated with 0, 1, 3 and 10 μM of indicated compounds for 14 d. Cell medium was changed with fresh full medium containing indicated compounds every 72h. The plates were then washed with PBS and stained with the solution containing 0.5% (w/v) crystal violet and 6% (v/v) glutaraldehyde for 30 min. The plates were then washed with running water until cell colonies were clear without background color and then dried at room temperature. Epson Perfection V600 Photo was used for the acquisition of the images. Quantitative Reverse Transcriptase Polymerase Chain Reaction (RT-qPCR). The RT-qPCR was performed as previously described. ^{47, 49} Briefly, NCI-H1299 p53Y220C stable cells were treated with DMSO or 10 μM of PK9328, Compound 17 or MS78 for 24 h. Total RNA was extracted using the Monarch Total RNA Miniprep Kit (T2010S, New England Biolabs), and cDNA was generated using the SuperScript IV First-Strand Synthesis System (18091050, Thermo Fisher). qPCR was performed using the PowerUp SYBR Green Master Mix (Thermo Fisher Scientific, A25742) on Agilent Technologies Stratagene Mx3005p qPCR system. RxnReady ^™ premixed primer pairs for p53, p21, TIGAR, BAX, PUMA and MDM2 were purchased from Integrated DNA Technologies, Inc. (Coralville, Iowa). GAPDH forward: 5?- ACAACTTTGGTATCGTGGAAGG-3?, GAPDH reverse: δ?- GCCATCACGCCACAGTTTC-3? was used as controls. The mRNA expression for each target gene was first normalized to internal GAPDH and then calculated relative to the DMSO control. Experiments were performed in triplicates. RNA-seq study. NCI-H1299 p53-null and p53Y220C stable cells were treated with DMSO or 10 μM of MS78 for 24h in quadruplicates. Cells were washed three times using ice-cold 1XPBS and subsequently pelleted by centrifuging at 12,000 rpm at 4°C. The pellet was flash frozen and sent to Azenta Life Sciences for further studies. The total RNA in 16 samples were extracted using Qiagen RNeasy Plus Mini Kit according to the protocols in the RNeasy Plus Mini Handbook published by Qiagen. RNA-seq libraries were constructed from the PolyA selected mRNA using the TruSeq RNA sample preparation guide (Illumina) and paired-end 150 base pairs sequencing on a HiSeq2500 system (Illumina) was performed at Azenta Life Sciences. The raw data in FASTQ format was analyzed as previously described. ⁵⁰ After quality control of FASTQ files using the FASTQC tool (version 0.11.7) (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/), we trimmed low-quality bases (Phred?δ?10) and adapter sequences and then discarded short reads (length? ?60?nt) using the bbduk tool (version 37.53) (https://jgi.doe.gov/data-and-tools/bbtools/bb- tools-user-guide/). When either forward or reverse of a paired-end read were discarded, we discarded the complete paired-end read. We quantified the expression of transcripts using cleaned paired-end reads with the Salmon tool (version 0.9.1) ⁵¹ using the human reference transcriptome from The Cancer Genome Atlas (TCGA; GDC.h38 GENCODE v22). ⁵² We performed the differential expression between the NCI- H1299 (p53Y220C) cell lines treated with DMSO or MS78 and the NCI-H1299 (p53-null) cell lines treated with DMSO or MS78 at gene level using the R tximport library (version 1.26.1) on R (version 4.2.2). ⁵³ We pre-filtered genes to keep only genes that had at least 10 reads in total (Ngene? ?22,454) and then performed differential gene expression using the R DESeq2 library (version 1.38.3). We identified as differential expressed between two conditions when the P value adjusted was at 5% and log2(fold change) was more than 1. The heatmap was drawn using the R ComplexHeatmap library (version 2.14.0). We next performed GSEA to capture pathways perturbed towards both directions simultaneously using the 22,454 ranked genes identified in our dataset and annotated in ENSEMBL (version 94) against the 343 p53 target genes listed in previously reported study ³⁹ using GSEAPreranked (version 4.3.2.; number of permutations = 1000, no collapse) and the KEGG pathways using R GAGE (version 2.48.0). Data Availability. RNA-seq data have been deposited in the GEO database (GEO accession no. GSE229576). There are no restrictions on data availability. Statistics and Reproducibility. Experimental data are presented as the mean ± SD or SEM of three independent experiments unless otherwise noted. Statistical analysis was performed using an unpaired two-sided Student’s t test for comparing two sets of data with assumed normal distribution. The results for immunoblotting are representative of at least three biologically independent experiments unless otherwise noted. All statistical analyses and visualizations were performed using GraphPad (Prism v8.4.2) and BioRender. Table S1: Characterization of p53Y220C and p300 driver genes using the Cancer Cell Line Encyclopedia (CCLE)1

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8. Yamazoe, S.; Tom, J.; Fu, Y.; Wu, W.; Zeng, L.; Sun, C.; Liu, Q.; Lin, I; Lin, K.; Fairbrother, W. J.; Staben, S. T., Heterobifunctional molecules induce dephosphorylation of Kinases-A proof of concept study. J. Med. Chem. 2020, 63 (6), 2807-2813.

9. Wang, W. W.; Chen, L. Y.; Wozniak, J. M.; Jadhav, A. M.; Anderson, H.; Malone, T. E.; Parker, C. G., Targeted protein acetylation in cells using heterobifunctional molecules. J. Am. Chem. Soc. 2021, 143 (40), 16700-16708.

10. Narita, T; Weinert, B. T.; Choudhary, C., Functions and mechanisms of nonhistone protein acetylation. Nat. Rev. Mol. Cell Biol. 2019, 20 (3), 156-174.

11. Chen, L.; Liu, S.; Tao, Y., Regulating tumor suppressor genes: post-translational modifications. Signal. Transduct. Target. Ther. 2020, 5 (1), 90.

12. Markham, D.; Munro, S.; Soloway, I; O'Connor, D. P.; La Thangue, N. B., DNA- damage-responsive acetylation of pRb regulates binding to E2F-1. EMBO Rep. 2006, 7 (2), 192- 198.

13. Ikenoue, T.; Inoki, K.; Zhao, B.; Guan, K. L., PTEN acetylation modulates its interaction with PDZ domain. Cancer Res. 2008, 68 (17), 6908-6912.

14. Liu, Y. ; Gu, W. , p53 in ferroptosis regulation: the new weapon for the old guardian. Cell Death Differ. 2022, 29 (5), 895-910.

15. Luo, J.; Li, M.; Tang, Y.; Laszkowska, M.; Roeder, R. G.; Gu, W., Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc. Natl. Acad. Sci. USA 2004, 101 (8), 2259-2264.

16. Tang, Y.; Zhao, W.; Chen, Y.; Zhao, Y.; Gu, W., Acetylation is indispensable for p53 activation. Ce//2008, 133 (4), 612-626.

17. Wang, S. J.; Li, D.; Ou, Y ; Jiang, L.; Chen, Y.; Zhao, Y.; Gu, W., Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression. Cell Rep. 2016, 17 (2), 366-373.

18. Nabet, B.; Roberts, J. M.; Buckley, D. L.; Paulk, J.; Dastjerdi, S.; Yang, A.; Leggett, A. L.; Erb, M. A.; Lawlor, M. A.; Souza, A.; Scott, T. G.; Vittori, S.; dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 2018, 14 (5), 431-441.

19. Yang, W.; Rozamus, L. W.; Narula, S.; Rollins, C. T.; Yuan, R.; Andrade, L. J.; Ram, M. K.; Phillips, T. B.; van Schravendijk, M. R.; Dalgamo, D.; Clackson, T.; Holt, D. A., Investigating protein-ligand interactions with a mutant FKBP possessing a designed specificity pocket. J. Med. Chem. 2000, 43 (6), 1135-1142.

20. Bullock, A. N. ; Henckel, J. ; Fersht, A. R. , Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy. Oncogene 2000, 19 (10), 1245-1256.

21. Boeckler, F. M.; Joerger, A. C.; Jaggi, G.; Rutherford, T. J.; Veprintsev, D. B.; Fersht, A. R., Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc. Natl. Acad. Set. U SA 2008, 105 (30), 10360-10365.

22. Wilcken, R.; Liu, X.; Zimmermann, M. O.; Rutherford, T. J.; Fersht, A. R.; Joerger, A. C.; Boeckler, F. M., Halogen-enriched fragment libraries as leads for drug rescue of mutant p53. J. Am. Chem. Soc. 2012, 134 (15), 6810-6818.

23. Liu, X ; Wilcken, R.; Joerger, A. C.; Chuckowree, I. S.; Amin, J.; Spencer, J.; Fersht, A. R., Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Res. 2013, 41 (12), 6034-6044.

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