Bulatov Emil, Zagidullin Almaz, Valiullina Aygul, Sayarova Regina, Rizvanov Albert
Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russia.
Front Pharmacol. 2018 May 8;9:450. doi: 10.3389/fphar.2018.00450. eCollection 2018.
Ubiquitin-proteasome system (UPS) is a primary signaling pathway for regulation of intracellular protein levels. E3 ubiquitin ligases, substrate-specific members of the UPS, represent highly attractive protein targets for drug discovery. The importance of E3 ligases as prospective targets for small molecule modulation is reinforced by ever growing evidence of their role in cancer and other diseases. To date the number of potent compounds targeting E3 ligases remains rather low and their rational design constitutes a challenging task. To successfully address this problem one must take into consideration the multi-subunit nature of many E3 ligases that implies multiple druggable pockets and protein-protein interfaces. In this review, we briefly cover the current state of drug discovery in the field of RING-type E3 ligases with focus on MDM and Cullin families as targets. We also provide an overview of small molecule chimeras that induce RING-type E3-mediated proteasomal degradation of substrate proteins of interest.
泛素-蛋白酶体系统（UPS）是调节细胞内蛋白质水平的主要信号通路。E3泛素连接酶作为UPS的底物特异性成员，是药物研发中极具吸引力的蛋白质靶点。越来越多的证据表明E3连接酶在癌症和其他疾病中的作用，这进一步凸显了其作为小分子调节剂潜在靶点的重要性。迄今为止，靶向E3连接酶的有效化合物数量仍然相当少，其合理设计是一项具有挑战性的任务。要成功解决这个问题，必须考虑到许多E3连接酶的多亚基性质，这意味着存在多个可成药口袋和蛋白质-蛋白质界面。在这篇综述中，我们简要介绍了以RING型E3连接酶为靶点的药物研发现状，重点关注MDM和Cullin家族。我们还概述了能够诱导RING型E3介导的感兴趣底物蛋白的蛋白酶体降解的小分子嵌合体。
