Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors

Wilson, Stuart C.; Atrash, Butrus; Barlow, Clare; Eccles, Susan; Fischer, Peter M.; Hayes, Angela; Kèlland, Lloyd R.; Jackson, Wayne; Jarman, Michael; Mirza, Amin; Moreno, Javier; Nutley, Bernard; Raynaud, Florence I.; Sheldrake, Peter; Walton, Mike I.; Westwood, R.; Whittaker, Steven R.; Workman, Paul; McDonald, Edward

doi:10.1016/j.bmc.2011.08.051

Cited by 32 publications

(39 citation statements)

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“…Cell lines were passaged for less than 6 months upon receipt. CCT068127 was synthesized as described (Wilson et al ., ) and solubilized in dimethyl sulfoxide to a stock concentration of 10 mmol·L −1 . The BCL2 family inhibitor ABT263 was purchased from Selleck Chemicals (Tse et al ., ).…”

Section: Methodsmentioning

confidence: 99%

“…We embarked upon a drug discovery program to develop CDK2 and 9 inhibitors that exhibited significantly improved pharmacological properties compared with the parental clinical drug seliciclib (CYC202, R‐roscovitine) (McClue et al ., ; Raynaud et al ., ; Whittaker et al ., ). To this end, we identified CCT068127, a novel trisubstituted purine with improved potency, selectivity, metabolic stability, and antitumor activity compared with seliciclib (Wilson et al ., ). Here, we describe the biochemical and cellular characterization of CCT068127 and identify synergistic drug combinations to further improve the efficacy of such CDK2/9 inhibitors for the treatment of colorectal cancer.…”

Section: Introductionmentioning

confidence: 97%

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

et al. 2018

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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

et al. 2018

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“…30 As described above (see Methods section), 1 was fragmented according to the SynDiR rules while retaining the central purine scaffold and N9-isopropyl moiety, consistent with the scope of the previously reported medicinal chemistry program ( Figure 4). 30 The MOARF DND workflow, including RATS alignment, was applied to the two remaining R-groups (R 2 and R 3 in Figure 4) with the query molecule defined by R 2 and R 3 = Me. Scoring of each solution used a set of ligand-based methods (ROCS, atom pair similarity, and predicted activity using an RF model), combined with a ClogP desirability function for each generated molecule.…”

Section: Journal Of Chemical Information and Modelingmentioning

confidence: 99%

MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation

Firth

Atrash

Brown

et al. 2015

J. Chem. Inf. Model.

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We describe the development and application of an integrated, multiobjective optimization workflow (MOARF) for directed medicinal chemistry design. This workflow couples a rule-based molecular fragmentation scheme (SynDiR) with a pharmacophore fingerprint-based fragment replacement algorithm (RATS) to broaden the scope of reconnection options considered in the generation of potential solution structures. Solutions are ranked by a multiobjective scoring algorithm comprising ligand-based (shape similarity) biochemical activity predictions as well as physicochemical property calculations. Application of this iterative workflow to optimization of the CDK2 inhibitor Seliciclib (CYC202, R-roscovitine) generated solution molecules in desired physicochemical property space. Synthesis and experimental evaluation of optimal solution molecules demonstrates CDK2 biochemical activity and improved human metabolic stability.

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“…This was frequently through the "design of structures that resemble purines and/or ATP itself and will bind at ATP-binding sites"; an approach that has been quite successful at producing structures for clinical trials. [27][28][29] In an alternative approach that did not formally concentrate on the specifics of the ATP-binding site, the Waldman group successfully utilized the components of BiOS to search for kinase inhibitors.…”

Section: Multiple Enzymatic Inhibitors From Relatively Simple Naturalmentioning

confidence: 99%

Making Sense of Structures by Utilizing Mother Nature's Chemical Libraries as Leads to Potential Drugs

Newman¹,

Cragg²

2014

Natural Products

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Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors

Cited by 32 publications

References 42 publications

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

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

MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation

Making Sense of Structures by Utilizing Mother Nature's Chemical Libraries as Leads to Potential Drugs

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