Abstract
Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.
MeSH terms
-
Cell Line, Tumor
-
Crystallography, X-Ray
-
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
-
Cyclin-Dependent Kinase 4 / chemistry
-
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
-
Cyclin-Dependent Kinase 6 / chemistry
-
High-Throughput Screening Assays
-
Humans
-
Kinetics
-
Models, Molecular*
-
Pyrazoles / chemical synthesis*
-
Pyrazoles / chemistry
-
Pyrazoles / pharmacology
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacology
-
Structure-Activity Relationship
Substances
-
Pyrazoles
-
Pyrimidines
-
Cyclin-Dependent Kinase 4
-
Cyclin-Dependent Kinase 6