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TitleDiscovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.
Journal, issue, pagesJ Am Chem Soc, Vol. 146, Issue 46, Page 31433-31443, Year 2024
Publish dateNov 20, 2024
AuthorsHlib 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 /
PubMed AbstractSmall 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 ...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-1 derivatives that target casein kinase 1 α (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 ideas to rationalize 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.
External linksJ Am Chem Soc / PubMed:39499896 / PubMed Central
MethodsEM (single particle)
Resolution3.81 - 4.2 Å
Structure data

EMDB-46922: WEE1 bound to CRBN-DDB1 via compound 10 (CRBN closed conformation)
Method: EM (single particle) / Resolution: 3.81 Å

EMDB-46923: WEE1 bound to CRBN-DDB1 via compound 10 (CRBN open conformation)
Method: EM (single particle) / Resolution: 4.2 Å

Source
  • Homo sapiens (human)

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