AbstractPharmacological reactivation of the tumor suppressor p53 remains a key challenge for the treatment of cancer. Acetylation Targeting Chimera (AceTAC), a novel technology is previously reported that hijacks lysine acetyltransferases p300/CBP to acetylate the p53Y220C mutant. However, p300/CBP are the only acetyltransferases harnessed for AceTAC development to date. In this study, it is demonstrated for the first time that the TAF1 acetyltransferase can be recruited to acetylate p53Y220C. A novel TAF1‐recruiting AceTAC, MS172 is discovered, which effectively acetylates p53Y220C lysine 382 in a concentration‐, time‐ and TAF1‐dependent manner via inducing the ternary complex formation between p53Y220C and TAF1. Notably, MS172 suppresses the proliferation in multiple p53Y220C‐harboring cancer cell lines more potently than the previously reported p300/CBP‐recruiting p53Y220C AceTAC MS78 with little toxicity in p53 WT and normal cells. Additionally, MS172 is bioavailable in mice and suitable for in vivo efficacy studies. Lastly, novel upregulation of metallothionine proteins by MS172‐induced p53Y220C acetylation is discovered using RNA‐seq and RT‐qPCR studies. This work demonstrates that TAF1 can be harnessed for AceTAC development and expands the very limited repertoire of the acetyltransferases that can be leveraged for developing AceTACs, thus advancing the targeted protein acetylation field.