Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library

  • J Am Chem Soc. 2024 Nov 20;146(46):31433-31443. doi: 10.1021/jacs.4c06127.
Hlib Razumkov  1  2 ,  Zixuan Jiang  1  2 ,  Kheewoong Baek  3  4 ,  Inchul You  2 ,  Qixiang Geng  2  5 ,  Katherine A Donovan  3  4 ,  Michelle T Tang  2 ,  Rebecca J Metivier  3  4 ,  Nada Mageed  3  4 ,  Pooreum Seo  2  5 ,  Zhengnian Li  2  5 ,  Woong Sub Byun  2  5 ,  Stephen M Hinshaw  2  5 ,  Roman C Sarott  2  5 ,  Eric S Fischer  3  4 ,  Nathanael S Gray  2  5
Affiliations
  • 1. Department of Chemistry, Stanford School of Humanities and Sciences, Stanford University, Stanford, California 94305, United States.
  • 2. Department of Chemical and Systems Biology, ChEM-H, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 5. Stanford Cancer Institute, Stanford School of Humanities and Sciences, Stanford University, Stanford, California 94305, United States.
PMID: 39499896 DOI: 10.1021/jacs.4c06127
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-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.

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