Michelle Tang

All Publications

• Ratiometric transcriptional activation by protein degradation. Cell Gray, M. A., Randal, K. L., Co, J. A., Tang, M. T., Xue, A. Z., Chen, S. W., Razumkov, H., Omran, Q. Q., Solow-Cordero, D. E., Yu, J., Robinson, S. A., Starnbach, C. A., Gray, N. S., Corsello, S. M., Banik, S. M. 2026

  Abstract

  Cells can respond to alterations in the abundances of specific proteins through transcriptional outputs. Synthetic approaches inspired by native post-transcriptional circuits that convert protein abundance changes into programmable gene expression would be transformative. Here, we discover and describe design principles that effectively convert protein degradation into transcriptional outputs in live cells. We define ratiometric transcriptional activation, where control over the ratio between a transcription factor and a protein of interest fused to its inhibitor enables detection of abundance changes with high sensitivity at scale. We show that ratiometric transcriptional activation can be implemented in single cells using triply orthogonal circuits or in multicellular pools, operating independently of the mechanism of protein downregulation and enabling simultaneous detection of multiple protein downregulation events through outputs such as cell survival, fluorescent protein expression, or barcode sequencing. These circuits can be applied to oncogenic targets and enable discovery of new molecular glue degraders.

  View details for DOI 10.1016/j.cell.2026.08.009

  View details for PubMedID 42679820

• Ratiometric transcriptional activation by protein degradation. bioRxiv : the preprint server for biology Gray, M. A., Randal, K. L., Co, J. A., Tang, M. T., Xue, A. Z., Chen, S. W., Razumkov, H., Omran, Q. Q., Solow-Cordero, D. E., Yu, J., Robinson, S. A., Starnbach, C. A., Gray, N. S., Corsello, S. M., Banik, S. M. 2026

  Abstract

  Cells can respond to alterations in the abundances of specific proteins through transcriptional outputs. Synthetic approaches inspired by native post-transcriptional circuits that convert protein abundance changes into programmable gene expression would be transformative. Here, we discover and describe design principles that effectively convert protein degradation into transcriptional outputs in live cells. We define ratiometric transcriptional activation, where control over the ratio between a transcriptional inhibitor-protein of interest fusion and transcription factor enables detection of abundance changes with high sensitivity at scale. We show that ratiometric transcriptional activation can be implemented in single cells using triply orthogonal circuits or in multicellular pools, operating independently of mechanism of protein downregulation and enabling simultaneous detection of multiple protein downregulation events through outputs such as cell survival, fluorescent protein expression, or barcode sequencing. These circuits can be applied to oncogenic targets and enable discovery of new molecular glue degraders.

  View details for DOI 10.64898/2026.05.16.725679

  View details for PubMedID 42239404

  View details for PubMedCentralID PMC13228303

• Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex. Cancer discovery Yuan, L., Ji, W., Dwyer, B. G., Lu, J., Bian, J., Colombo, G. M., Martinez, M. J., Fernandez, D., Phillips, N. A., Tang, M. T., Zhou, C. W., Quispe Calla, N. E., Guzman Huancas, C., Eckart, M., Tran, J., Jones, H. M., Qiu, T., Doench, J. G., Rees, M. G., Roth, J. A., Cameron, M. D., Charville, G. W., Kuo, C. J., Dixon, S. J., Zhang, T., Hinshaw, S. M., Gray, N. S., Corsello, S. M. 2025

  Abstract

  Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex. Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the nuclear pore complex. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and x-ray crystallography, while compound-induced TRIM21-nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and in vitro. Phenotype-guided optimization yielded compounds with 10-fold greater potency and drug-like properties with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids.

  View details for DOI 10.1158/2159-8290.CD-25-0271

  View details for PubMedID 40891634

• Development of Potent and Selective CK1α Molecular Glue Degraders. Journal of medicinal chemistry Geng, Q., Jiang, Z., Byun, W. S., Donovan, K. A., Zhuang, Z., Jiang, F., Jones, H. M., Razumkov, H., Tang, M. T., Sarott, R. C., Fischer, E. S., Corsello, S. M., Hinshaw, S. M., Gray, N. S. 2025

  Abstract

  Molecular glue degraders (MGDs) are small molecules that facilitate proximity between a target protein and an E3 ubiquitin ligase, thereby inducing target protein degradation. Glutarimide-containing compounds are MGDs that bind cereblon (CRBN) and recruit neosubstrates. Through explorative synthesis of a glutarimide-based library, we discovered a series of molecules that induce casein kinase 1 alpha (CK1α) degradation. By scaffold hopping and rational modification of the chemical scaffold, we identified an imidazo[1,2-a]pyrimidine compound that induces potent and selective CK1α degradation. A structure-activity relationship study of the lead compound, QXG-6442, identified the chemical features that contribute to degradation potency and selectivity compared to other frequently observed neosubstrates. The glutarimide library screening and structure-activity relationship medicinal chemistry approach we employed is generally useful for developing new molecular glue degraders toward new targets of interest.

  View details for DOI 10.1021/acs.jmedchem.4c02415

  View details for PubMedID 39873536

• 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