Stanford Advisors

All Publications

  • 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

  • Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7). European journal of medicinal chemistry Ji, W., Du, G., Jiang, J., Lu, W., Mills, C. E., Yuan, L., Jiang, F., He, Z., Bradshaw, G. A., Chung, M., Jiang, Z., Byun, W. S., Hinshaw, S. M., Zhang, T., Gray, N. S. 2024; 276: 116613

    Abstract

    Cyclin-dependent kinase 7, along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs cell cycle progression via T-loop phosphorylation of cell cycle CDKs. Pharmacological inhibition of CDK7 leads to selective anti-cancer effects in cellular and in vivo models, motivating several ongoing clinical investigations of this target. Current CDK7 inhibitors are either reversible or covalent inhibitors of its catalytic activity. We hypothesized that small molecule targeted protein degradation (TPD) might result in differentiated pharmacology due to the loss of scaffolding functions. Here, we report the design and characterization of a potent CDK7 degrader that is comprised of an ATP-competitive CDK7 binder linked to a CRL2VHL recruiter. JWZ-5-13 effectively degrades CDK7 in multiple cancer cells and leads to a potent inhibition of cell proliferation. Additionally, compound JWZ-5-13 displayed bioavailability in a pharmacokinetic study conducted in mice. Therefore, JWZ-5-13 is a useful chemical probe to investigate the pharmacological consequences of CDK7 degradation.

    View details for DOI 10.1016/j.ejmech.2024.116613

    View details for PubMedID 39004018