发现调节E3泛素连接酶的药物的方法。

J Huang, L Tsvetkov, K Qu, S Daniel-Issakani, D G Payan
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引用次数: 2

摘要

泛素-蛋白酶体系统(UPS)在多种细胞调控信号通路中起着重要作用。蛋白酶体抑制剂Velcade在治疗几种人类癌症中的临床效果强调了UPS作为药物干预新靶点的重要性。E3泛素连接酶是调节和决定特定底物泛素化的关键酶复合物,其异常调节与多种疾病表型有关。靶向选择性E3连接酶可能允许对不同途径进行特异性操作,并最终导致更好的治疗指数和减少非特异性副作用。在这里,我们的目的是讨论在这类靶标中干扰小分子的挑战,以及E3连接酶药物发现的当前策略和进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Approaches to discovering drugs that regulate E3 ubiquitin ligases.

The ubiquitin-proteasome system (UPS) plays an essential role in a wide variety of cell regulatory signaling pathways. The clinical effectiveness of the proteasome inhibitor Velcade in the treatment of several human cancers underscores the importance of the UPS as a novel target area for pharmaceutical intervention. E3 ubiquitin ligases are key enzyme complexes that regulate and determine the ubiquitination of specific substrates, whose abnormal regulation has been implicated in multiple disease phenotypes. Targeting a selective E3 ligase may allow specific manipulation of distinct pathways and eventually lead to a better therapeutic index with reduced nonspecific side effects. Here, we aim to discuss the challenges of interfering with small molecules in this target class, as well as current strategies and progress in E3 ligase drug discovery.

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