A patent review of the ubiquitin ligase system: 2015-2018
A patent review of the ubiquitin ligase system: 2015-2018
复制标题
泛素连接酶系统专利审查：2015-2018
DOI：
10.1080/13543776.2018.1549229
复制
发表时间：
2018-12-02
影响因子：
6.6
通讯作者：
Dou, Q. Ping
中科院分区：
文献类型：
--
作者：
Li, Xin;Elmira, Ekinci;Dou, Q. Ping
前言：泛素-蛋白酶体系统(UPS)是近20年来被证实的一种新型抗癌药物靶点。UPS包括两个不同的步骤：泛素激活酶(E1)、泛素结合酶(E2)和泛素连接酶(E3)对底物蛋白质的泛素化，以及26S蛋白酶体复合体对底物的降解。E3酶是泛素化步骤的中心参与者，在癌细胞中具有广泛的特定底物，为发现和开发选择性药物提供了巨大的机会。涉及的领域：本综述总结了E1s、E2s和E3s小分子抑制剂的最新进展，重点介绍了E3抑制剂和调节剂的最新专利(从2015年到2018年)。专家观点：克服目前20S蛋白酶体抑制剂局限性的一个策略是发现UPS上游关键组件的抑制剂，如E3酶。E3S在肿瘤的发生发展中起着重要的作用，决定了底物泛素化的特异性，提供了新的靶向机会。E3调节剂可以通过合理设计、天然化合物或文库筛选、旧药再利用以及其他新技术的应用来开发。进一步了解E3-底物相互作用的机制对于发现和开发下一代E3抑制剂作为有效的抗癌药物是至关重要的。
Introduction: Ubiquitin-proteasome system (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), and substrate degradation by the 26S proteasome complex. The E3 enzyme is the central player in the ubiquitination step and has a wide range of specific substrates in cancer cells, offering great opportunities for discovery and development of selective drugs. Areas covered: This review summarizes the recent advances in small molecule inhibitors of E1s, E2s, and E3s, with a focus on the latest patents (from 2015 to 2018) of E3 inhibitors and modulators. Expert opinion: One strategy to overcome limitations of current 20S proteasome inhibitors is to discover inhibitors of the upstream key components of the UPS, such as E3 enzymes. E3s play important roles in cancer development and determine the specificity of substrate ubiquitination, offering novel target opportunities. E3 modulators could be developed by rational design, natural compound or library screening, old drug repurposes, and application of other novel technologies. Further understanding of mechanisms of E3-substrate interaction will be essential for discovering and developing next-generation E3 inhibitors as effective anticancer drugs.