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.
Christine M Richardson  1 ,  Claire L Nunns ,  Douglas S Williamson ,  Martin J Parratt ,  Pawel Dokurno ,  Rob Howes ,  Jenifer Borgognoni ,  Martin J Drysdale ,  Harry Finch ,  Roderick E Hubbard ,  Philip S Jackson ,  Peter Kierstan ,  Georg Lentzen ,  Jonathan D Moore ,  James B Murray ,  Heather Simmonite ,  Allan E Surgenor ,  Christopher J Torrance
Affiliations
PMID: 17570665 DOI: 10.1016/j.bmcl.2007.04.110
Abstract

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.