恢复基因组的监护权：逆转致癌突变 p53 错误折叠的抗癌药物策略。

Restoring guardianship of the genome: Anticancer drug strategies to reverse oncogenic mutant p53 misfolding.

机构信息

Laboratory of Experimental and Molecular Neuroimaging (LEMNI), Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Drive, Grant S-047, Stanford, CA 94305, USA.

Cellular Pathway Imaging Laboratory (CPIL), Molecular Imaging Program at Stanford, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA 94305, USA.

出版信息

Cancer Treat Rev. 2018 Dec;71:19-31. doi: 10.1016/j.ctrv.2018.09.004. Epub 2018 Sep 20.

DOI:10.1016/j.ctrv.2018.09.004

PMID:30336366

Abstract

p53 is a transcription factor that activates numerous genes involved in essential maintenance of genetic stability. P53 is the most frequently mutated gene in human cancer. One third of these mutations are structural, resulting in mutant p53 with a disrupted protein conformation. Here we review current progress in a relatively underexplored aspect of p53-targeted drug development, that is, strategies to reactivate wild-type function of misfolded mutant p53. Unfortunately, most p53-targeted drugs are still at early stages of development and many of them are progressing slowly toward clinical implementation. Significant challenges need to be addressed before clinical translation of new anti-misfolding p53-targeted drugs.

摘要

p53 是一种转录因子，可激活参与遗传稳定性基本维持的众多基因。p53 是人类癌症中最常发生突变的基因。这些突变中有三分之一为结构性突变，导致突变 p53 的蛋白构象被破坏。本文综述了 p53 靶向药物开发中一个相对较少被探索的方面的最新进展，即重新激活错误折叠的突变 p53 的野生型功能的策略。遗憾的是，大多数 p53 靶向药物仍处于开发早期，其中许多药物在向临床应用推进方面进展缓慢。在新型抗 p53 错构药物向临床转化之前，还需要解决许多重大挑战。