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.
Subject(s)
Cyclin-Dependent Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Crystallography, X-Ray , Drug Design , Protein Kinase Inhibitors/chemistryABSTRACT
Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3beta (GSK-3beta). One example had a CDK2 IC(50) of 120 nM and showed selectivity over GSK-3beta of 167-fold.
Subject(s)
Cyclin-Dependent Kinase 2/antagonists & inhibitors , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Triazoles/chemistry , Cell Line, Tumor , Cyclin-Dependent Kinase 2/metabolism , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3beta and other kinases.