2. Academic Validation
  3. Acetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53

Acetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53

  • J Am Chem Soc. 2023 Jul 12;145(27):14932-14944. doi: 10.1021/jacs.3c04640.
Md Kabir 1,  Ning Sun 1,  Xiaoping Hu 1,  Tiphaine C Martin 2,  Jingjie Yi 3,  Yue Zhong 2,  Yan Xiong 1,  H Ümit Kaniskan 1,  Wei Gu 3,  Ramon Parsons 2,  Jian Jin 1 2
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
  • 2 Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
  • 3 Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
PMID: 37365684 DOI: 10.1021/jacs.3c04640
Abstract

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 Ace tylation Ta rgeting C himera (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 mutation with little toxicity in Cancer cells with wild-type p53. RNA-seq studies revealed novel p53Y220C-dependent upregulation of TRAIL apoptotic genes and downregulation of DNA damage response pathways upon acetylation induced by MS78. Altogether, the AceTAC strategy could provide a generalizable platform for targeting proteins, such as tumor suppressors, via acetylation.

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