发现能够在体外和体内使 p53 突变体重新激活的化合物。
Discovery of compounds that reactivate p53 mutants in vitro and in vivo.
机构信息
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA.
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
出版信息
Cell Chem Biol. 2022 Sep 15;29(9):1381-1395.e13. doi: 10.1016/j.chembiol.2022.07.003. Epub 2022 Aug 10.
The tumor suppressor p53 is the most frequently mutated protein in human cancer. The majority of these mutations are missense mutations in the DNA binding domain of p53. Restoring p53 tumor suppressor function could have a major impact on the therapy for a wide range of cancers. Here we report a virtual screening approach that identified several small molecules with p53 reactivation activities. The UCI-LC0023 compound series was studied in detail and was shown to bind p53, induce a conformational change in mutant p53, restore the ability of p53 hotspot mutants to associate with chromatin, reestablish sequence-specific DNA binding of a p53 mutant in a reconstituted in vitro system, induce p53-dependent transcription programs, and prevent progression of tumors carrying mutant p53, but not p53 or p53 alleles. Our study demonstrates feasibility of a computation-guided approach to identify small molecule corrector drugs for p53 hotspot mutations.
抑癌基因 p53 是人类癌症中最常发生突变的蛋白。这些突变大多数是 p53 DNA 结合域的错义突变。恢复 p53 肿瘤抑制功能可能会对广泛的癌症治疗产生重大影响。在这里，我们报告了一种虚拟筛选方法，该方法鉴定出了几种具有 p53 再激活活性的小分子。详细研究了 UCI-LC0023 化合物系列，结果表明该化合物能够与 p53 结合，诱导突变型 p53 的构象变化，恢复 p53 热点突变体与染色质结合的能力，在重建的体外系统中重新建立 p53 突变体的序列特异性 DNA 结合，诱导 p53 依赖性转录程序，并阻止携带突变型 p53 的肿瘤进展，但不能阻止 p53 或 p53 等位基因。我们的研究证明了通过计算指导的方法来鉴定 p53 热点突变的小分子校正药物是可行的。
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