ABSTRACT
A novel series of oxindole-type inhibitors of CDK2 that have heteroatom substituted alkynyl moieties at their C-4 position is described. These novel 4-alkynyl-substituted inhibitors have superior potency relative to their parent compound in free enzyme and in cell based assays. The crystal structure of CDK2 in complex with one of these analogues was determined and gives insight to their increased potency. The biochemical evaluation of a representative derivative is also described.
Subject(s)
CDC2-CDC28 Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase 2 , DNA/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Indoles/chemistry , Models, Molecular , Molecular Conformation , Paclitaxel/pharmacology , Structure-Activity RelationshipABSTRACT
A series of oxindole CDK2 inhibitors was synthesized. These novel analogues have a saturated monosubstituted cyclic moiety at their C-4 position that mimics the ribofuranoside of ATP. This substitution afforded agents with increased potency relative to the parent indolinone and nanomolar range IC(50) against the CDK2 enzyme and two cancer cell lines.
