Michelle Tang

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

• Covalent Targeting of Glutamate Cysteine Ligase to Inhibit Glutathione Synthesis. Chembiochem : a European journal of chemical biology Zhang, L. H., Tang, M., Tao, X., Shao, Q., Thomas, V., Shimizu, S., Kasano, M., Ishikawa, Y., Inukai, T., Nomura, D. K. 2023; 24 (23): e202300371

  Abstract

  Dysregulated oxidative stress plays a major role in cancer pathogenesis and some types of cancer cells are particularly vulnerable to inhibition of their cellular antioxidant capacity. Glutamate-cysteine ligase (GCL) is the first and rate-limiting step in the synthesis of the major cellular antioxidant glutathione (GSH). Developing a GCL inhibitor may be an attractive therapeutic strategy for certain cancer types that are particularly sensitive to oxidative stress. In this study, we reveal a cysteine-reactive ligand, EN25, that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, and leads to inhibition of GCL activity. This interaction also leads to reduced cellular GSH levels and impaired cell viability in ARID1A-deficient cancer cells, which are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells. Our studies uncover a novel potential ligandable site within GCLM that can be targeted to inhibit GSH synthesis in vulnerable cancer cell types.

  View details for DOI 10.1002/cbic.202300371

  View details for PubMedID 37756477

  View details for PubMedCentralID PMC10739677