Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
J Med Chem. 2024 Aug 22;67(16):14633-14648. doi: 10.1021/acs.jmedchem.4c01497. Epub 2024 Aug 6.
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 (). 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. 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, is a potentially valuable chemical tool to investigate the role of p53Y220C acetylation in cancer.
著名的肿瘤抑制因子 p53 在大约一半的癌症中发生突变。Y220C 突变是 p53 热点突变之一。已经开发了几种 p53Y220C 的小分子稳定剂。我们最近开发了一种诱导靶向蛋白乙酰化的新技术，称为乙酰化靶向嵌合体（AceTAC），并开发了第一个有效乙酰化 p53Y220C 赖氨酸 382 的 p53Y220C AceTAC。在这里，我们报告了 p53Y220C AceTAC 的构效关系（SAR）研究，该研究发现了一种新型的 p53Y220C AceTAC，化合物 ()。通过诱导 p300/CBP 乙酰转移酶和 p53Y220C 的三元复合物形成，以时间和浓度依赖的方式有效地将 p53Y220C 乙酰化在赖氨酸 382 上。在携带 p53Y200C 突变的癌细胞中，比母体 p53Y220C 稳定剂更有效地抑制增殖和集落形成，并且在小鼠中具有生物利用度。总体而言，是一种有潜力的化学工具，可以研究 p53Y220C 乙酰化在癌症中的作用。
