Hlib Razumkov

All Publications

• Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library. Journal of the American Chemical Society Razumkov, H., Jiang, Z., Baek, K., You, I., Geng, Q., Donovan, K. A., Tang, M. T., Metivier, R. J., Mageed, N., Seo, P., Li, Z., Byun, W. S., Hinshaw, S. M., Sarott, R. C., Fischer, E. S., Gray, N. S. 2024

  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.

  View details for DOI 10.1021/jacs.4c06127

  View details for PubMedID 39499896