Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor

Whittaker, Steven R. and Barlow, Clare and Martin, Matthew P. and Mancusi, Caterina and Wagner, Steve and Self, Annette and Barrie, Elaine and te Poele, Robert and Sharp, Swee and Brown, Nathan and Wilson, Stuart and Jackson, Wayne and Fischer, Peter M. and Clarke, Paul A. and Walton, Michael I. and McDonald, Edward and Blagg, Julian and Noble, Martin and Garrett, Michelle D. and Workman, Paul (2017) Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. Molecular Oncology . ISSN 1878-0261 (In Press)

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Abstract

Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimised from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 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 CDK2 is the likely mechanism of greater enzymatic potency. Commensurate with inhibition of CDK activity, CCT068127 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 CCT068127 shows greatest similarity to other small molecule CDK and also HDAC inhibitors. CCT068127 caused a dramatic loss in expression of DUSP6 phosphatase, alongside elevated ERK phosphorylation and activation of MAPK pathway target genes. MCL1 protein levels are rapidly decreased by CCT068127 treatment and this associates with synergistic antiproliferative activity after combined treatment with CCT068127 and ABT263, a BCL2-family inhibitor. These findings support the rational combination of this series of CDK2/9 inhibitors and BCL2 family inhibitors for the treatment of human cancer.

Item Type: Article
Keywords: CDK, MCL1, seliciclib, CCT068127, ABT263
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: 10.1002/1878-0261.12148
Depositing User: Fischer, Professor Peter
Date Deposited: 26 Oct 2017 14:58
Last Modified: 26 Oct 2017 18:00
URI: http://eprints.nottingham.ac.uk/id/eprint/47586

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