Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor

Bioorg Med Chem Lett. 2014 Jan 1;24(1):199-203. doi: 10.1016/j.bmcl.2013.11.041. Epub 2013 Nov 23.


A new class of quinoline-based kinase inhibitors has been discovered that both disrupt cyclin dependent 2 (CDK2) interaction with its cyclin A subunit and act as ATP competitive inhibitors. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the monomer CDK2 in an affinity-selection/mass spectrometry-based technique and to perform secondary assays that identified compounds that bound only to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Kd) of the original hit improved from 1 to 0.005μM.

Keywords: CDK2; High throughput screening; Kinases; Modulator; Tumor.

MeSH terms

  • Crystallography, X-Ray
  • Cyclin A / antagonists & inhibitors*
  • Cyclin A / chemistry
  • Cyclin A / metabolism
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 2 / chemistry
  • Cyclin-Dependent Kinase 2 / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship


  • Cyclin A
  • Protein Kinase Inhibitors
  • Quinolines
  • quinoline
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2