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

Whittaker, Steven R.; Barlow, Clare; Martin, Matthew 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

Authors

Steven R. Whittaker

Clare Barlow

Matthew P. Martin

Caterina Mancusi

Steve Wagner

Annette Self

Elaine Barrie

Robert te Poele

Swee Sharp

Nathan Brown

Stuart Wilson

Wayne Jackson

Peter M. Fischer peter.fischer@nottingham.ac.uk

Paul A. Clarke

Michael I. Walton

Edward McDonald

Julian Blagg

Martin Noble

Michelle D. Garrett

Paul Workman



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.

Citation

Whittaker, S. R., Barlow, C., Martin, M. P., Mancusi, C., Wagner, S., Self, A., …Workman, P. (in press). Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. Molecular Oncology, 12(3), https://doi.org/10.1002/1878-0261.12148

Journal Article Type Article
Acceptance Date Oct 7, 2017
Online Publication Date Jan 28, 2018
Deposit Date Oct 26, 2017
Publicly Available Date Jan 28, 2018
Journal Molecular Oncology
Print ISSN 1574-7891
Electronic ISSN 1878-0261
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 12
Issue 3
DOI https://doi.org/10.1002/1878-0261.12148
Keywords CDK, MCL1, seliciclib, CCT068127, ABT263
Public URL http://eprints.nottingham.ac.uk/id/eprint/47586
Publisher URL http://onlinelibrary.wiley.com/doi/10.1002/1878-0261.12148/abstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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