Chasing molecular glue degraders: screening approaches,Chemical Society Reviews

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Chasing molecular glue degraders: screening approaches
Chemical Society Reviews ( IF 40.4 ) Pub Date : 2022-06-20 , DOI: 10.1039/d2cs00197g
Ana Domostegui ₁ , Luis Nieto-Barrado ₁ , Carles Perez-Lopez ₁ , Cristina Mayor-Ruiz ₁

Affiliation

Protein–protein interactions (PPIs) govern all biological processes. Some small molecules modulate PPIs through induced protein proximity. In particular, molecular glue degraders are monovalent compounds that orchestrate interactions between a target protein and an E3 ubiquitin ligase, prompting the proteasomal degradation of the former. This and other pharmacological strategies of targeted protein degradation (e.g. proteolysis-targeting chimeras – PROTACs) overcome some limitations of traditional occupancy-based therapeutics. Here, we provide an overview of the “molecular glue” concept, with a special focus on natural and synthetic inducers of proximity to E3s. We then briefly highlight the serendipitous discoveries of some clinical and preclinical molecular glue degraders, and discuss the first examples of intentional discoveries. Specifically, we outline the different screening strategies reported in this rapidly evolving arena and our thoughts on future perspectives. By mastering the ability to influence PPIs, molecular glue degraders can induce the degradation of unligandable proteins, thus providing an exciting path forward to broaden the targetable proteome.

中文翻译：

追逐分子胶降解剂：筛选方法

蛋白质-蛋白质相互作用 (PPI) 支配着所有的生物过程。一些小分子通过诱导蛋白质接近来调节 PPI。特别是，分子胶降解剂是一种单价化合物，可协调靶蛋白和 E3 泛素连接酶之间的相互作用，促进前者的蛋白酶体降解。这种和其他靶向蛋白质降解的药理学策略（例如蛋白水解靶向嵌合体——PROTACs）克服了传统的基于占用的疗法的一些限制。在这里，我们概述了“分子胶”的概念，特别关注与 E3 接近的天然和合成诱导剂。然后，我们简要介绍了一些临床和临床前分子胶降解剂的偶然发现，并讨论了有意发现的第一个例子。具体来说，我们概述了在这个快速发展的领域中报告的不同筛选策略以及我们对未来观点的看法。通过掌握影响 PPI 的能力，分子胶降解剂可以诱导不可配位蛋白的降解，从而为拓宽可靶向蛋白质组提供了一条令人兴奋的途径。

更新日期：2022-06-20

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