Design, synthesis and biological evaluation of pyrimidine derivatives as novel CDK2 inhibitors that induce apoptosis and cell cycle arrest in breast cancer cells

Bioorg Med Chem. 2018 Jul 23;26(12):3491-3501. doi: 10.1016/j.bmc.2018.05.024. Epub 2018 May 17.

Abstract

Cyclin-dependent kinase 2 (CDK2) plays a key role in eukaryotic cell cycle progression which could facilitate the transition from G1 to S phase. The dysregulation of CDK2 is closely related to many cancers. CDK2 is utilized as one of the most studied kinase targets in oncology. In this article, 24 benzamide derivatives were designed, synthesized and investigated for the inhibition activity against CDK2. Our results revealed that the compound 25 is a potent CDK2 inhibitor exhibiting a broad spectrum anti-proliferative activity against several human breast cancer cells. Additionally, compound 25 could block cell cycle at G0 or G1 and induce significant apoptosis in MDA-MB-468 cells. These findings highlight a rationale for further development of CDK2 inhibitors to treat human breast cancer.

Keywords: Anti-proliferative activity; Apoptosis; CDK2 inhibitor; Cell cycle arrest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Binding Sites
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Drug Design*
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship
  • Thermodynamics
  • bcl-2-Associated X Protein / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • bcl-2-Associated X Protein
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Caspase 3