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

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. 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.

SUBMITTER: Whittaker SR

PROVIDER: S-EPMC5830651 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Whittaker Steven R SR Barlow Clare C Martin Mathew P MP Mancusi Caterina C Wagner Steve S Self Annette A Barrie Elaine E Te Poele Robert R Sharp Swee S Brown Nathan N Wilson Stuart S Jackson Wayne W Fischer Peter M PM Clarke Paul A PA Walton Michael I MI McDonald Edward E Blagg Julian J Noble Martin M Garrett Michelle D MD Workman Paul P

Molecular oncology 20180128 3

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 agai ...[more]

PMID: 29063678

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Project description:BackgroundColorectal cancer is common to both sexes; third in terms of morbidity and second in terms of mortality, accounting for 10% and 9.2% of cancer cases in men and women globally. Although drugs such as bevacizumab, Camptosar, and cetuximab are being used to manage colorectal cancer, the efficacy of the drugs has been reported to vary from patient to patient. These drugs have also been reported to have varying degrees of side effects; thus, the need for novel drug therapies with better efficacy and lesser side effects. In silico drugs design methods provide a faster and cost-effect method for lead identification and optimization. The aim of this study, therefore, was to design novel imidazol-5-ones via in silico design methods.ResultsA QSAR model was built using the genetic function algorithm method to model the cytotoxicity of the compounds against the HCT116 colorectal cancer cell line. The built model had statistical parameters; R2 = 0.7397, R2adj = 0.6712, Q2cv = 0.5547, and R2ext. = 0.7202 and revealed the cytotoxic activity of the compounds to be dependent on the molecular descriptors nS, GATS5s, VR1_Dze, ETA_dBetaP, and L3i. These molecular descriptors were poorly correlated (VIF < 4.0) and made unique contributions to the built model. The model was used to design a novel set of derivatives via the ligand-based drug design approach. Compounds e, h, j, and l showed significantly better cytotoxicity (IC50 < 5.0 μM) compared to the template. The interaction of the compounds with the CDK2 enzyme (PDB ID: 6GUE) was investigated via molecular docking study. The compounds were potent inhibitors of the enzyme having binding affinity of range -10.8 to -11.0 kcal/mol and primarily formed hydrogen bond interaction with lysine, aspartic acid, leucine, and histidine amino acid residues of the enzyme.ConclusionThe QSAR model built was stable, robust, and had a good predicting ability. Thus, predictions made by the model were reliably employed in further in silico studies. The compounds designed were more active than the template and showed better inhibition of the CDK2 enzyme compared to the standard drugs sorafenib and kenpaullone.

Dataset Information

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

Publications

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

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