Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents

Eur J Med Chem. 2013:70:447-55. doi: 10.1016/j.ejmech.2013.08.052. Epub 2013 Sep 15.

Abstract

A series of 2,4,5-trisubstituted pyrimidines have been synthesised and characterised, which exhibited potent CDK inhibition and anti-proliferative activities. The structure-activity relationship is analysed and a rational for CDK9 selectivity is discussed. Compound 9s, possessing appreciable selectivity for CDK9 over other CDKs, is capable of activating caspase 3, reducing the level of Mcl-1 anti-apoptotic protein, and inducing cancer cell apoptosis.

Keywords: Anti-cancer drug discovery; CDK9 inhibitors; Inhibitor design; Mcl-1 anti-apoptotic proteins; RNA polymerase II.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • Humans
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Cyclin-Dependent Kinases
  • pyrimidine