Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitors

Abstract—A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity againstCDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in theCDK1 assay (IC 50 <10nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carriedout with a CDK1 homology model, and provide a rationale for the observed activities. 2005 Elsevier Ltd. All rights reserved. Thecyclin-dependentkinases(CDKs)representafamilyof serine–threonine protein kinases, which control cellcycle progression in proliferating eukaryotic cells. 1 CDK activity is dependent on the presence of cyclinpartners,whoselevelsareregulatedinasequentialman-ner to ensure that the phases of the cell cycle proceed inthe correct order. 2 Perturbations in CDK function andconsequent loss of cell cycle regulation have been di-rectly linked to the molecular pathology of cancer. 3 Asa result of the strong association between the CDKsand cancer biology, efforts have been aimed towardsthe development of CDK inhibitors for the treatmentof cancer.