Molecular profiling and combinatorial activity of CCT 068127: a potent CDK 2 and CDK 9 inhibitor

Deregulation of the cyclin‐dependent kinases ( CDK s) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDK s have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT 068127, a novel inhibitor of CDK 2 and CDK 9. Optimized from the purine template of seliciclib, CCT 068127 exhibits greater potency and selectivity against purified CDK 2 and CDK 9 and superior antiproliferative activity against human colon cancer and melanoma cell lines. X‐ray crystallography studies reveal that hydrogen bonding with the DFG motif of CDK 2 is the likely mechanism of greater enzymatic potency. Commensurate with inhibition of CDK activity, CCT 068127 treatment results in decreased retinoblastoma protein ( RB ) phosphorylation, reduced phosphorylation of RNA polymerase II , and induction of cell cycle arrest and apoptosis. The transcriptional signature of CCT 068127 shows greatest similarity to other small‐molecule CDK and also HDAC inhibitors. CCT 068127 caused a dramatic loss in expression of DUSP 6 phosphatase, alongside elevated ERK phosphorylation and activation of MAPK pathway target genes. MCL 1 protein levels are rapidly decreased by CCT 068127 treatment and this associates with synergistic antiproliferative activity after combined treatment with CCT 068127 and ABT 263, a BCL 2 family inhibitor. These findings support the rational combination of this series of CDK 2/9 inhibitors and BCL 2 family inhibitors for the treatment of human cancer.