胶水
计算生物学
计算机科学
化学
生物
材料科学
复合材料
作者
Hlib Razumkov,Zixuan Jiang,Kheewoong Baek,Inchul You,Qixiang Geng,Katherine A. Donovan,Michelle T. Tang,Rebecca J. Metivier,Nada Mageed,Pooreum Seo,Zhengnian Li,Woong Sub Byun,Stephen M. Hinshaw,Roman C. Sarott,Eric S. Fischer,Nathanael S. Gray
标识
DOI:10.1101/2024.05.04.592550
摘要
Abstract Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While Cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-01 derivatives that target casein kinase 1 alpha (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and a rationale for the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.
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