Acetylation targeting chimera enables acetylation of the tumor suppressor p53
Open accessAbstract
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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Development of an acetylation targeting chimera (AceTAC) targeting p53 acetylation has shown promising results, while other attempts to target the p53-Mdm2 interaction have struggled.
“development of an acetylation targeting chimera (AceTAC) targeting p53 acetylation has shown promising results, while other attempts to target the p53-Mdm2 interaction thus far have struggled [39–41].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [40]
The Introduction and Conclusions (page not available) report that the AceTAC compound MS78 acetylated the p53Y220C mutant and suppressed growth of cancer cells carrying that mutation, supporting the promising-results portion. The paper does not report that attempts to target the p53–Mdm2 interaction have struggled; its discussion of Mdm2 concerns gene expression, not that interaction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAceTAC MS78 targets disease-relevant p53 mutant p53Y220C and recruits p300 to induce p53 acetylation and subsequent stabilization and activation to promote tumor-suppressor activity.
“AceTAC MS78 targets disease-relevant p53 mutant p53Y220C and recruits p300 to induce p53 acetylation and subsequent stabilization and activation to promote tumor-suppressor activity of p53 [40].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [40]
The Conclusions and §2.2 report that MS78 brings p53Y220C together with p300 and induces its acetylation. Section 2.2 also reports stabilization of p53Y220C, while the Introduction and Conclusions describe p53-dependent growth suppression. However, the paper presents stabilization as an effect of MS78 binding; it does not establish the claimed sequence in which acetylation leads to subsequent stabilization. (LLM, conf=0.87)
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- Authors
- Kabir, M., Sun, N., Hu, X., Martin, T. C., Yi, J., Zhong, Y., Xiong, Y., Kaniskan, H. Ü., Gu, W., Parsons, R., & Jin, J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Tisch Cancer Institute (US)
- Herbert Irving Comprehensive Cancer Center (US)
- Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Corresponding author
- Jin, Jian
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2023-06-26
- Volume
- 145
- Issue
- 27
- Pages
- 14932-14944
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC10357929
- OpenAlex
- W4382181400
- Cited by
- 65
- References
- 54
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 18 · 2023: 4
- FWCI
- 5.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (T32CA078207)
- Icahn School of Medicine at Mount Sinai
- National Institutes of Health (1S10OD025132, 1S10OD028504)
- National Institute of General Medical Sciences (T32GM062754)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p53, CBP/p300, histone acetyltransferase, tumor suppressor activation, DNA damage response, tumor cell proliferation
- MeSH terms
- Acetylation, Humans, Models, Molecular, Mutation, Protein Processing, Post-Translational, Tumor Suppressor Protein p53, Protein Structure, Tertiary, Cell Line, Tumor
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