环亚胺:受 Degron 启发的脑龙结合剂,用于靶向降解蛋白质

IF 6.6 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Saki Ichikawa , N. Connor Payne , Wenqing Xu , Chia-Fu Chang , Nandini Vallavoju , Spencer Frome , Hope A. Flaxman , Ralph Mazitschek , Christina M. Woo
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引用次数: 0

摘要

脑龙(Cereblon,CRBN)是一种 E3 连接酶底物适配器,被广泛用于靶向蛋白质降解(TPD)策略。然而,实现高效和有选择性的目标降解是与 CRBN 结合的配体面临的一个突出挑战。在这里,我们报告了从 CRBN C 端环状亚胺脱胶子衍生的配体环亚胺,它们与 CRBN 的相互作用模式各不相同,为开发强效和选择性双功能降解剂提供了一种简便的方法。基于 TR-FRET 对不同底物的二元和三元复合物中的 60 种环亚胺降解剂进行定量表征后发现,三元复合物的结合亲和力与细胞降解效率密切相关。我们的研究确立了环亚胺作为 TPD 多用途弹头的独特性质,以及量化三元复合物形成以预测其细胞降解活性的系统生化方法,这两项研究将共同加速开发能与 CRBN 结合的配体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The cyclimids: Degron-inspired cereblon binders for targeted protein degradation

The cyclimids: Degron-inspired cereblon binders for targeted protein degradation

The cyclimids: Degron-inspired cereblon binders for targeted protein degradation

Cereblon (CRBN) is an E3 ligase substrate adapter widely exploited for targeted protein degradation (TPD) strategies. However, achieving efficient and selective target degradation is a preeminent challenge with ligands that engage CRBN. Here, we report that the cyclimids, ligands derived from the C-terminal cyclic imide degrons of CRBN, exhibit distinct modes of interaction with CRBN and offer a facile approach for developing potent and selective bifunctional degraders. Quantitative TR-FRET-based characterization of 60 cyclimid degraders in binary and ternary complexes across different substrates revealed that ternary complex binding affinities correlated strongly with cellular degradation efficiency. Our studies establish the unique properties of the cyclimids as versatile warheads in TPD and a systematic biochemical approach for quantifying ternary complex formation to predict their cellular degradation activity, which together will accelerate the development of ligands that engage CRBN.

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来源期刊
Cell Chemical Biology
Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍: Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.
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