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.

中文翻译：

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cyclimids：受德格隆启发的 cereblon 结合剂，用于靶向蛋白质降解

Cereblon (CRBN) 是一种 E3 连接酶底物适配器，广泛用于靶向蛋白质降解 (TPD) 策略。然而，对于与 CRBN 结合的配体来说，实现有效和选择性的目标降解是一个巨大的挑战。在此，我们报道了环酰亚胺（源自 CRBN C 端环状酰亚胺降解决定子的配体）表现出与 CRBN 的独特相互作用模式，并为开发有效且选择性的双功能降解剂提供了一种简便的方法。对不同基质的二元和三元复合物中的 60 种环酰胺降解剂进行基于 TR-FRET 的定量表征表明，三元复合物结合亲和力与细胞降解效率密切相关。我们的研究确立了cyclimids作为TPD中的多功能弹头的独特性质，以及用于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，这将加速与CRBN结合的配体的开发。