Characterization of a Pyrazolo[4,3-d]pyrimidine Inhibitor of Cyclin-Dependent Kinases 2 and 5 and Aurora A With Pro-Apoptotic and Anti-Angiogenic Activity In Vitro

Chem Biol Drug Des. 2015 Dec;86(6):1528-40. doi: 10.1111/cbdd.12618. Epub 2015 Sep 16.

Abstract

Selective inhibitors of kinases that regulate the cell cycle, such as cyclin-dependent kinases (CDKs) and aurora kinases, could potentially become powerful tools for the treatment of cancer. We prepared and studied a series of 3,5,7-trisubstituted pyrazolo[4,3-d]pyrimidines, a new CDK inhibitor scaffold, to assess their CDK2 inhibitory and antiproliferative activities. A new compound, 2i, which preferentially inhibits CDK2, CDK5, and aurora A was identified. Both biochemical and cellular assays indicated that treatment with compound 2i caused the downregulation of cyclins A and B, the dephosphorylation of histone H3 at Ser10, and the induction of mitochondrial apoptosis in the HCT-116 colon cancer cell line. It also reduced migration as well as tube and lamellipodia formation in human endothelial cells. The kinase inhibitory profile of compound 2i suggests that its anti-angiogenic activity is linked to CDK5 inhibition. This dual mode of action involving apoptosis induction in cancer cells and the blocking of angiogenesis-like activity in endothelial cells offers possible therapeutic potential.

Keywords: angiogenesis; apoptosis; aurora A; cyclin-dependent kinase; inhibitor; pyrazolo[4,3-d]pyrimidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Aurora Kinase A / antagonists & inhibitors*
  • Cell Cycle / drug effects
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase Inhibitor Proteins / chemical synthesis
  • Cyclin-Dependent Kinase Inhibitor Proteins / chemistry
  • Cyclin-Dependent Kinase Inhibitor Proteins / pharmacology
  • Drug Design
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor Proteins
  • Protein Kinase Inhibitors
  • AURKA protein, human
  • Aurora Kinase A
  • Cyclin-Dependent Kinase 5
  • CDK2 protein, human
  • CDK5 protein, human
  • Cyclin-Dependent Kinase 2