Related Experiment Video

Updated: Jun 21, 2025

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
12:26

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

18.6K

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

Wenzhi Ji1, Guangyan Du2, Jie Jiang2

  • 1Department of Chemical and Systems Biology, Chem-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.

European Journal of Medicinal Chemistry
|July 14, 2024
PubMed

Insights

Targeted protein degradation of cyclin-dependent kinase 7 (CDK7) with novel compound JWZ-5-13 effectively degrades CDK7, inhibiting cancer cell proliferation and showing bioavailability in mice.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclin-dependent kinase 7 (CDK7) is part of the CDK-activating complex (CAK), crucial for cell cycle progression.
  • CDK7 inhibition shows anti-cancer effects, with ongoing clinical trials targeting this enzyme.
  • Existing CDK7 inhibitors target catalytic activity; this study explores targeted protein degradation (TPD).

Purpose of the Study:

  • To design and characterize a novel small molecule for targeted protein degradation of CDK7.
  • To investigate if TPD of CDK7 offers differentiated pharmacology compared to catalytic inhibition.
  • To evaluate the anti-cancer efficacy and pharmacokinetic properties of a new CDK7 degrader.

Main Methods:

  • Design of a bifunctional molecule linking a CDK7 binder to a CRL2-VHL E3 ligase recruiter.
  • Characterization of the compound's ability to degrade CDK7 in various cancer cell lines.
  • Assessment of cell proliferation inhibition and in vivo pharmacokinetic studies in mice.

Main Results:

  • A potent CDK7 degrader, JWZ-5-13, was successfully designed and synthesized.
  • JWZ-5-13 effectively degraded CDK7 in multiple cancer cell lines.
  • The compound demonstrated significant inhibition of cancer cell proliferation and showed oral bioavailability in mice.

Conclusions:

  • Targeted protein degradation is a viable strategy for inhibiting CDK7.
  • JWZ-5-13 is a potent chemical probe for studying CDK7 degradation's pharmacological effects.
  • This approach may offer new therapeutic avenues for cancer treatment.
Keywords:
CDK7PROTACProtein degraderSelective

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