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

DOI: 10.1002/1878-0261.12148 DOI Help

Authors: Steven R. Whittaker (The Institute of Cancer Research) , Clare Barlow (The Institute of Cancer Research) , Mathew Martin (Newcastle University) , Caterina Mancusi (The Institute of Cancer Research) , Steve Wagner (The Institute of Cancer Research) , Annette Self (The Institute of Cancer Research) , Elaine Barrie (The Institute of Cancer Research) , Robert Te Poele (The Institute of Cancer Research) , Swee Sharp (The Institute of Cancer Research) , Nathan Brown (The Institute of Cancer Research) , Stuart Wilson (The Institute of Cancer Research) , Wayne Jackson (Cyclacel Ltd) , Peter M. Fischer (Cyclacel Ltd) , Paul A. Clarke (The Institute of Cancer Research) , Michael I. Walton (The Institute of Cancer Research) , Edward Mcdonald (The Institute of Cancer Research) , Julian Blagg (The Institute of Cancer Research) , Martin Noble (Newcastle University) , Michelle D. Garrett (The Institute of Cancer Research) , Paul Workman (The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Oncology

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 9948

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.

Journal Keywords: CDK; MCL1; seliciclib; CCT068127; ABT263

Subject Areas: Biology and Bio-materials, Medicine


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