2. Academic Validation
  3. Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7)

Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7)

  • Eur J Med Chem. 2024 Jun 27:276:116613. doi: 10.1016/j.ejmech.2024.116613.
Wenzhi Ji 1,  Guangyan Du 2,  Jie Jiang 2,  Wenchao Lu 1,  Caitlin E Mills 3,  Linjie Yuan 1,  Fen Jiang 1,  Zhixiang He 2,  Gary A Bradshaw 3,  Mirra Chung 3,  Zixuan Jiang 1,  Woong Sub Byun 1,  Stephen M Hinshaw 1,  Tinghu Zhang 4,  Nathanael S Gray 5
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Chem-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
  • 3 Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA.
  • 4 Department of Chemical and Systems Biology, Chem-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA. Electronic address: ztinghu8@stanford.edu.
  • 5 Department of Chemical and Systems Biology, Chem-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA. Electronic address: nsgray01@stanford.edu.
PMID: 39004018 DOI: 10.1016/j.ejmech.2024.116613
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.

Keywords

CDK7; PROTAC; Protein degrader; Selective.

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