Advances in molecular glues: exploring chemical space and design principles for targeted protein degradation

IF 6.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Hemant Kumar S , Muthukumaran Venkatachalapathy , Ramesh Sistla , Vasanthanathan Poongavanam
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引用次数: 0

Abstract

The discovery of the E3 ligase cereblon (CRBN) as the target of thalidomide and its analogs revolutionized the field of targeted protein degradation (TPD). This ubiquitin-mediated degradation pathway was first harnessed by bivalent degraders. Recently, the emergence of low-molecular-weight molecular glue degraders (MGDs) has expanded the TPD landscape, because MGDs operate via the same mechanism while offering attractive physicochemical properties that are consistent with small-molecule therapeutics. This review delves into the discovery and advancement of MGDs, with case studies on cyclin K and the zinc finger protein IKZF2, highlighting the design principles, biological assays and therapeutic applications. Additionally, it examines the chemical space of molecular glues and outlines the collaborative efforts that are fueling innovation in this field.
分子胶的进展:探索定向降解蛋白质的化学空间和设计原则。
E3 连接酶脑龙(CRBN)是沙利度胺及其类似物的靶标,这一发现彻底改变了靶向蛋白质降解(TPD)领域。这种泛素介导的降解途径首先被二价降解器所利用。最近,低分子量分子胶降解剂(MGDs)的出现扩大了 TPD 的范围,因为 MGDs 通过相同的机制运作,同时具有与小分子疗法一致的诱人理化特性。本综述通过对细胞周期蛋白 K 和锌指蛋白 IKZF2 的案例研究,深入探讨了 MGDs 的发现和发展,重点介绍了其设计原理、生物检测和治疗应用。此外,它还研究了分子胶的化学空间,并概述了推动该领域创新的合作努力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Drug Discovery Today
Drug Discovery Today 医学-药学
CiteScore
14.80
自引率
2.70%
发文量
293
审稿时长
6 months
期刊介绍: Drug Discovery Today delivers informed and highly current reviews for the discovery community. The magazine addresses not only the rapid scientific developments in drug discovery associated technologies but also the management, commercial and regulatory issues that increasingly play a part in how R&D is planned, structured and executed. Features include comment by international experts, news and analysis of important developments, reviews of key scientific and strategic issues, overviews of recent progress in specific therapeutic areas and conference reports.
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