期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 21, 页码 14513-14543出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00851
关键词
-
This study developed novel nonphthalimide CRBN binders by optimizing physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features. These binders exhibited enhanced chemical stability and favorable selectivity in neosubstrate recruitment, providing opportunities for the design of highly selective and potent chemically inert compounds.
Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据