Fen Jiang

All Publications

• 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 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