Advancing targeted protein degradation for cancer therapy.
Advancing targeted protein degradation for cancer therapy.
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DOI：
10.1038/s41568-021-00365-x
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Dale B;Cheng M;Park KS;Kaniskan HÜ;Xiong Y;Jin J
人类蛋白质组包含约20,000个蛋白质，估计有600多个蛋白质对各种类型的癌症具有重要的功能，其中包括近400个非酶蛋白质，这些蛋白质是传统占有率驱动的药理学难以达到的靶点。小分子降解物，包括分子胶和非双功能降解物，如蛋白水解靶向嵌合体(PROTAC)的最新进展，使许多以前被认为不可用药的蛋白质成为可能。特别是，PROTACs与被劫持的E3 ubiluitin连接酶和靶蛋白形成三元复合体，导致靶蛋白的多糖基化和降解。这种方法的广泛适用性是由于单个E3连接酶识别不同底物的灵活性所促进的。人类约600个E3连接酶中的绝大多数还没有被探索，因此为开发针对具有组织、肿瘤和亚细胞选择性的癌蛋白的降解剂提供了巨大的机会。在这篇综述中，我们首先讨论了靶向蛋白质降解的分子基础。然后，我们提供了一个全面的帐户，最有希望的降解物在开发作为癌症疗法迄今。最后，我们概述了这一令人兴奋的领域的机遇和挑战。
The human proteome contains approximately 20,000 proteins, and it is estimated that more than 600 of them are functionally important for various types of cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional occupancy-driven pharmacology. Recent advances in the development of small-molecule degraders, including molecular glues and heterobifunctional degraders such as proteolysis-targeting chimeras (PROTACs), have made it possible to target many proteins that were previously considered undruggable. In particular, PROTACs form a ternary complex with a hijacked E3 ubiguitin ligase and a target protein, leading to polyubiguitination and degradation of the target protein. The broad applicability of this approach is facilitated by the flexibility of individual E3 ligases to recognize different substrates. The vast majority of the approximately 600 human E3 ligases have not been explored, thus presenting enormous opportunities to develop degraders that target oncoproteins with tissue, tumour and subcellular selectivity. In this Review, we first discuss the molecular basis of targeted protein degradation. We then offer a comprehensive account of the most promising degraders in development as cancer therapies to date. Lastly, we provide an overview of opportunities and challenges in this exciting field.
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影响因子：
6.2
作者：
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