从沙利度胺到靶向蛋白质降解的合理分子胶设计

IF 11.2 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Vladas Oleinikovas, Pablo Gainza, Thomas Ryckmans, Bernhard Fasching, Nicolas H Thomä
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引用次数: 0

摘要

沙利度胺及其衍生物是强大的癌症治疗药物,也是人们最了解的分子胶降解剂(MGDs)之一。这些药物可选择性地重新编程 E3 泛素连接酶 cereblon (CRBN),将目标蛋白质交由泛素蛋白酶体系统降解。MGDs 可在 E3 连接酶表面创建新的识别界面,从而与新基质发生诱导的蛋白质-蛋白质相互作用。对其作用机制的分子洞察为通过特定的识别图案(G-环)与大量靶标相互作用提供了令人兴奋的机会。我们的分析表明,目前基于 CRBN 的 MGD 原则上可以识别人类蛋白质组中 2500 多种含有 G 环的蛋白质。我们回顾了最近在调整 CRBN 与其 MGD 诱导的新底物之间的特异性方面取得的进展,并推导出了一套管理这些相互作用的简单规则。我们的结论是,合理的 MGD 设计工作将使更多的蛋白质得到选择性降解,从而将这种治疗方式扩展到更多的疾病领域。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation.

Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates. Molecular insight into their mechanism of action opens exciting opportunities to engage a plethora of targets through a specific recognition motif, the G-loop. Our analysis shows that current CRBN-based MGDs can in principle recognize over 2,500 proteins in the human proteome that contain a G-loop. We review recent advances in tuning the specificity between CRBN and its MGD-induced neosubstrates and deduce a set of simple rules that govern these interactions. We conclude that rational MGD design efforts will enable selective degradation of many more proteins, expanding this therapeutic modality to more disease areas.

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来源期刊
CiteScore
27.80
自引率
0.00%
发文量
53
期刊介绍: Since 1961, the Annual Review of Pharmacology and Toxicology has been a comprehensive resource covering significant developments in pharmacology and toxicology. The journal encompasses various aspects, including receptors, transporters, enzymes, chemical agents, drug development science, and systems like the immune, nervous, gastrointestinal, cardiovascular, endocrine, and pulmonary systems. Special topics are also featured in this annual review.
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