Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor
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 inhi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Published: |
Wiley
2018
|
| Subjects: | |
| Online Access: | https://eprints.nottingham.ac.uk/47586/ |
| _version_ | 1848797583046082560 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Whittaker, Steven R. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:06:11Z |
| format | Article |
| id | nottingham-47586 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:06:11Z |
| publishDate | 2018 |
| publisher | Wiley |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-475862020-05-04T19:28:43Z https://eprints.nottingham.ac.uk/47586/ 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 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. Wiley 2018-01-28 Article PeerReviewed 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. and Workman, Paul (2018) Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. Molecular Oncology, 12 (3). pp. 287-304. ISSN 1878-0261 CDK MCL1 seliciclib CCT068127 ABT263 http://onlinelibrary.wiley.com/doi/10.1002/1878-0261.12148/abstract doi:10.1002/1878-0261.12148 doi:10.1002/1878-0261.12148 |
| spellingShingle | CDK MCL1 seliciclib CCT068127 ABT263 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 Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor |
| title | Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor |
| title_full | Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor |
| title_fullStr | Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor |
| title_full_unstemmed | Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor |
| title_short | Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor |
| title_sort | molecular profiling and combinatorial activity of cct068127: a potent cdk2 and cdk9 inhibitor |
| topic | CDK MCL1 seliciclib CCT068127 ABT263 |
| url | https://eprints.nottingham.ac.uk/47586/ https://eprints.nottingham.ac.uk/47586/ https://eprints.nottingham.ac.uk/47586/ |