Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping

Bioorg Med Chem Lett. 2007 Jul 15;17(14):3880-5. doi: 10.1016/j.bmcl.2007.04.110. Epub 2007 May 6.


Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.

MeSH terms

  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Drug Design
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*


  • Protein Kinase Inhibitors
  • Cyclin-Dependent Kinase 2