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Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1
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Development of selective mono or dual PROTAC degrader probe of CDK isoforms

Fei Zhou1, Luyu Chen1, Chaoguo Cao1

  • 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.

European Journal of Medicinal Chemistry
|December 18, 2019
PubMed

Insights

Researchers developed Proteolysis Targeted Chimeras (PROTACs) to degrade cyclin-dependent kinases (CDKs). A dual-degrader compound F3 effectively reduced CDK2 and CDK9 levels, inhibiting prostate cancer cell proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cyclin-dependent kinases (CDKs) are crucial regulators of cell cycle and transcription.
  • Targeting CDKs offers therapeutic potential but faces challenges due to off-target toxicities.
  • Existing CDK inhibitors often exhibit toxicity issues, hindering clinical development.

Purpose of the Study:

  • To design and optimize Proteolysis Targeted Chimeras (PROTACs) for targeted degradation of multiple CDKs.
  • To evaluate the efficacy of novel PROTAC compounds in inhibiting cancer cell proliferation.
  • To explore PROTAC-mediated degradation of CDK2 and CDK9 as a therapeutic strategy.

Main Methods:

  • Design and synthesis of heterobifunctional small molecules utilizing the PROTAC approach.
  • Assessment of compound-induced degradation of target CDKs in cancer cells.
  • Evaluation of cell proliferation inhibition and cell cycle phase distribution.

Main Results:

  • Compound A9 selectively degraded CDK2.
  • Dual-degrader compound F3 potently induced degradation of both CDK2 (DC50: 62 nM) and CDK9 (DC50: 33 nM).
  • Compound F3 inhibited proliferation of human prostate cancer PC-3 cells by blocking the cell cycle in S and G2/M phases.

Conclusions:

  • PROTAC technology enables the development of potent and selective CDK degraders.
  • Targeted degradation of CDK2 and CDK9 via PROTACs shows promise as an effective anti-cancer therapeutic strategy.
  • This approach may overcome limitations associated with conventional CDK inhibitors, reducing off-target toxicity.
Keywords:
CDK2CDK9Cell cyclePROTACProstate cancer

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