Open AccessMolecular profiling and combinatorial activity of CCT 068127: a potent CDK 2 and CDK 9 inhibitor
Author(s) -
Whittaker Steven R.,
Barlow Clare,
Martin Mathew P.,
Mancusi Caterina,
Wagner Steve,
Self Annette,
Barrie Elaine,
Te Poele Robert,
Sharp Swee,
Brown Nathan,
Wilson Stuart,
Jackson Wayne,
Fischer Peter M.,
Clarke Paul A.,
Walton Michael I.,
McDonald Edward,
Blagg Julian,
Noble Martin,
Garrett Michelle D.,
Workman Paul
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12148
Subject(s) - cyclin dependent kinase , cdk inhibitor , kinase , biology , phosphorylation , microbiology and biotechnology , cell cycle , cancer research , biochemistry , chemistry , apoptosis
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.