Design, Synthesis, and Evaluation of p53Y220C Acetylation Targeting Chimeras (AceTACs)
- PMID: 39169826
- PMCID: PMC11378941
- DOI: 10.1021/acs.jmedchem.4c01497
Design, Synthesis, and Evaluation of p53Y220C Acetylation Targeting Chimeras (AceTACs)
Abstract
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.
Figures
References
-
- Joerger AC; Fersht AR Structural biology of the tumor suppressor p53 and cancer-associated mutants. Adv. Cancer. Res 2007, 97, 1–23. - PubMed
-
- Natarajan A; Babikir HA; Paulmurugan R; Massoud TF Small Molecules Targeting Misfolded Mutants of p53 as a Rescue Strategy to Improve Glioblastoma Chemotherapy. In Glioblastoma Resistance to Chemotherapy: Molecular Mechanisms and Innovative Reversal Strategies; Academic Press, 2021; pp 749–771.
-
- Duffy MJ; Crown J Drugging “undruggable” genes for cancer treatment: Are we making progress? Int. J. Cancer 2021, 148, 8–17. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Research Materials