Design, synthesis, and evaluation of p53Y220C acetylation targeting chimeras (AceTACs)
Open accessAbstract
The well-known tumor suppressor p53 is mutated in approximately half of all cancers. The Y220C mutation is one of the major p53 hotspot mutations. Several small-molecule stabilizers of p53Y220C have been developed. We recently developed a new technology for inducing targeted protein acetylation, termed acetylation targeting chimera (AceTAC), and the first p53Y220C AceTAC that effectively acetylated p53Y220C at lysine 382. Here, we report structure–activity relationship (SAR) studies of p53Y220C AceTACs, which led to the discovery of a novel p53Y220C AceTAC, compound 11 ( MS182 ). 11 effectively acetylated p53Y220C at lysine 382 in a time- and concentration-dependent manner via inducing the ternary complex formation between p300/CBP acetyltransferase and p53Y220C. 11 was more effective than the parent p53Y220C stabilizer in suppressing the proliferation and clonogenicity in cancer cells harboring the p53Y200C mutation and was bioavailable in mice. Overall, 11 is a potentially valuable chemical tool to investigate the role of p53Y220C acetylation in cancer.
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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 [41]
The Introduction and Conclusions (page not provided) report that p53Y220C AceTACs induced acetylation and suppressed growth in cancer cell lines, supporting the description of promising results. The cited paper does not address whether attempts to target the p53–Mdm2 interaction have struggled; a search for Mdm2 found no relevant passage. (LLM, conf=0.85)
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Acetylation: a new target for protein degradation in cancer
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- Authors
- Hu, X., Kabir, M., Lin, Y., Xiong, Y., Parsons, R. E., Gu, W., & Jin, J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Tisch Cancer Institute (US)
- Herbert Irving Comprehensive Cancer Center (US)
- Corresponding author
- Jin, Jian
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2024-08-06
- Volume
- 67
- Issue
- 16
- Pages
- 14633-14648
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC11378941
- OpenAlex
- W4401353543
- Cited by
- 9
- References
- 24
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 1
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1S10OD025132, 1S10OD028504, T32CA078207)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- 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
- Keywords
- p53 acetylation, ternary complex formation, p53 hotspot mutations, structure-activity relationship, antiproliferative activity, bioavailability, cancer cells
- MeSH terms
- Acetylation, Animals, Antineoplastic Agents, Humans, Mutation, Structure-Activity Relationship, Drug Design, Tumor Suppressor Protein p53, Cell Line, Tumor, Cell Proliferation, p300-CBP Transcription Factors, Mice
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