Development of selective mono or dual PROTAC degrader probe of CDK isoforms

Eur J Med Chem. 2020 Feb 1:187:111952. doi: 10.1016/j.ejmech.2019.111952. Epub 2019 Dec 6.

Abstract

Cyclin-dependent kinase (CDK) family members are promising molecular targets in discovering potent inhibitors in disease settings, they function differentially. CDK2, CDK4 and CDK6, directly regulate the cell cycle, while CDK9 primarily modulates the transcription regulation. In discovering inhibitors of these CDKs, toxicity associated with off-target effect on other CDK homologs often posts as a clinical issue and hinders their further therapeutic development. To improve efficacy and reduce toxicity, here, using the Proteolysis Targeted Chimeras (PROTACs) approach, we design and further optimize small molecule degraders targeting multiple CDKs. We showed that heterobifunctional compound A9 selectively degraded CDK2. We also identified a dual-degrader, compound F3, which potently induced degradation of both CDK2 (DC50: 62 nM) and CDK9 (DC50: 33 nM). In human prostate cancer PC-3 cells, compound F3 potently inhibits cell proliferation by effectively blocking the cell cycle in S and G2/M phases. Our preliminary data suggests that PROTAC-oriented CDK2/9 degradation is potentially an effective therapeutic approach.

Keywords: CDK2; CDK9; Cell cycle; PROTAC; Prostate cancer.

MeSH terms

  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Structure
  • PC-3 Cells
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proteolysis / drug effects*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Isoenzymes
  • Protein Kinase Inhibitors
  • Cyclin-Dependent Kinases