biostudies-literatureKabir MNCATS NIH HHSNational Cancer InstituteNCI NIH HHSNational Institutes of HealthNational Institute of General Medical SciencesIcahn School of Medicine at Mount SinaiNIH HHSNIGMS NIH HHS14932-14944https://www.ebi.ac.uk/biostudies/studies/S-EPMC10357929biostudies-literatureUnknown145(27)With advances in chemically induced proximity technologies, heterobifunctional modalities such as proteolysis targeting chimeras (PROTACs) have been successfully advanced to clinics for treating cancer. However, pharmacologic activation of tumor-suppressor proteins for cancer treatment remains a major challenge. Here, we present a novel Acetylation Targeting Chimera (AceTAC) strategy to acetylate the p53 tumor suppressor protein. We discovered and characterized the first p53Y220C AceTAC, MS78, which recruits histone acetyltransferase p300/CBP to acetylate the p53Y220C mutant. MS78 effectively acetylated p53Y220C lysine 382 (K382) in a concentration-, time-, and p300-dependent manner and suppressed proliferation and clonogenicity of cancer cells harboring the p53Y220C mJournal of the American Chemical SocietyAcetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53.PMC10357929R35 CA220491T32 GM0627541S10OD025132T32GM062754UL1 TR004419S10 OD0251321S10OD028504T32 CA078207T32CA078207S10 OD028504Yi JXiong YSun NKaniskan HUHu XGu WZhong YParsons RKabir MJin JMartin TCfalseAcetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53.With advances in chemically induced proximity technologies, heterobifunctional modalities such as proteolysis targeting chimeras (PROTACs) have been successfully advanced to clinics for treating cancer. However, pharmacologic activation of tumor-suppressor proteins for cancer treatment remains a major challenge. Here, we present a novel Acetylation Targeting Chimera (AceTAC) strategy to acetylate the p53 tumor suppressor protein. We discovered and characterized the first p53Y220C AceTAC, MS78, which recruits histone acetyltransferase p300/CBP to acetylate the p53Y220C mutant. MS78 effectively acetylated p53Y220C lysine 382 (K382) in a concentration-, time-, and p300-dependent manner and suppressed proliferation and clonogenicity of cancer cells harboring the p53Y220C m2023-01-01T00:00:00Z2023 Jul2025-04-05T15:48:13.414Z2025-04-05T15:48:13.414ZS-EPMC103579293736568410.1021/jacs.3c04640