PO.CH01.01 · 化学
新型疏水性CRBN结合剂的设计与应用
Design and applications of novel hydrophobic CRBN binders
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
Cereblon（CRBN）分子胶降解剂通过一个浅结合口袋结合靶蛋白，是扩展可成药蛋白质组的一种有前景的策略。然而，基于结构发现CRBN分子胶的一个关键挑战在于CRBN-底物界面所诱导的构象多样性。不同的CRBN结合剂可以以不同的方式调节该界面，最终决定招募哪些底物蛋白并界定化合物的选择性。在本研究中，我们设计并鉴定了几种新型CRBN结合剂，它们表现出优异或可接受的二元结合亲和力。与先前报道的CRBN配体相比，我们的化合物具有独特的结构特征和增强的疏水性。基于这些骨架的衍生物使得能够构建一个延伸至先前未探索的、CRBN偏向性化学空间的CRBN分子胶文库。该文库提供了一个高质量的工具箱，以加速利用CRBN分子胶降解剂方法发现新靶点。
查看英文原文 English abstract
Cereblon (CRBN) molecular glue degraders engage target proteins through a shallow binding pocket, representing a promising strategy to expand the druggable proteome. However, a key challenge in the structure-based discovery of CRBN molecular glues lies in the conformational diversity induced at the CRBN-substrate interface. Different CRBN binders can modulate this interface in distinct ways, ultimately determining which substrate proteins are recruited and defining compound selectivity.In this study, we designed and identified several novel CRBN binders exhibiting excellent or acceptable binary binding affinities. Compared with previously reported CRBN ligands, our compounds possess unique structural features and enhanced hydrophobic properties. Derivatives based on these scaffolds enabled the construction of a CRBN molecular glue library that extends into previously unexplored, CRBN-biased chemical space. This library provides a high-quality toolbox to accelerate the discovery of new targets using the CRBN molecular glue degrader approach.
利益披露 Disclosure
H. Yang, None..
Q. Xu, None..
Y. Wang, None..
Z. Wu, None..
H. Zhang, None.