Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors

Bioorg Med Chem Lett. 2003 Jun 2;13(11):1939-42. doi: 10.1016/s0960-894x(03)00312-3.

Abstract

Cyclin-dependent kinases (CDKs) are essential in the control of cell cycle progression. Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases, especially cancer. Based on the crystal structure of CDK2 in complex with an imidazole indolinone compound 1 (SU9516), lead optimization through modeling, synthesis, and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent CDK2 inhibitors.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • CDC2-CDC28 Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 2
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Lactams / chemistry*
  • Lactams / pharmacology
  • Lactones / chemistry*
  • Lactones / pharmacology
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Indoles
  • Lactams
  • Lactones
  • imidazole
  • Adenosine Triphosphate
  • CDC2-CDC28 Kinases
  • Cyclin-Dependent Kinase 2