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

Lookup NU author(s): Dr Mathew Martin, Professor Martin Noble

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. 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. Optimized 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.


Publication metadata

Author(s): Whittaker SR, Barlow C, Martin MP, Mancusi C, Wagner S, Self A, Barrie E, Te Poele R, Sharp S, Brown N, Wilson S, Jackson W, Fischer PM, Clarke PA, Walton MI, McDonald E, Blagg J, Noble M, Garrett MD, Workman P

Publication type: Article

Publication status: Published

Journal: Molecular Oncology

Year: 2018

Volume: 12

Issue: 3

Pages: 287-304

Print publication date: 01/03/2018

Online publication date: 24/10/2017

Acceptance date: 07/10/2017

Date deposited: 12/03/2018

ISSN (print): 1574-7891

ISSN (electronic): 1878-0261

Publisher: John Wiley and Sons Ltd.

URL: https://doi.org/10.1002/1878-0261.12148

DOI: 10.1002/1878-0261.12148


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