Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor

Deng, Yongqi; Shipps, Gerald W.; Zhao, Long; Siddiqui, M. Arshad; Popovici‐Muller, Janeta; Curran, Patrick J.; Duca, José S.; Hruza, Alan; Fischmann, Thierry O.; Madison, Vincent; Zhang, Rumin; McNemar, Charles; Mayhood, Todd; Syto, Rosalinda; Annis, Allen; Kirschmeier, Paul T.; Lees, Emma; Windsor, William

doi:10.1016/j.bmcl.2013.11.041

Cited by 19 publications

(24 citation statements)

References 17 publications

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“…Therefore, attention is increasingly being focused on cell cycle, as a potential target for therapeutic intervention [35, 57, 58]. In this context, our finding that aspirin and salicylic acid down-regulate cyclin A2 /CDK2 protein and mRNAs in multiple cancer cell lines should initiate new thinking and research on these age-old drugs in cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Dachineni

Kumar

et al. 2016

Molecular Cancer Research

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Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin as a chemopreventive agent; however, the mechanisms leading to its anti-cancer effects are still being elucidated. We hypothesized that aspirin’s chemopreventive actions may involve cell cycle regulation through modulation of the levels or activity of cyclin A2/cyclin dependent kinase-2 (CDK2). In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The down regulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. Firstly, inclusion of salicylic acid in naïve cell lysates, or in recombinant CDK2 preparations, increased the ability of the anti-CDK2 antibody to immunoprecipitate CDK2, suggesting that salicylic acid may directly bind and alter its conformation. Secondly, in 8-anilino-1-naphthalene-sulfonate (ANS)-CDK2 fluorescence assays, pre-incubation of CDK2 with salicylic acid, dose-dependently quenched the fluorescence due to ANS. Thirdly, computational analysis using molecular docking studies identified Asp145 and Lys33 as the potential sites of salicylic acid interactions with CDK2. These results demonstrate that aspirin and salicylic acid down-regulate cyclin A2/CDK2 proteins in multiple cancer cell lines, suggesting a novel target and mechanism of action in chemoprevention. Implications Biochemical and structural studies indicate that the anti-proliferative actions of aspirin are mediated through cyclin A2/CDK2.

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Section: Discussionmentioning

confidence: 99%

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Dachineni

Kumar

et al. 2016

Molecular Cancer Research

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“…3D) and represent a second distinct class of CDK inhibitors. A third group of CDK2 inhibitors includes compounds that alter the folding of CDK2 such that it modulates cyclin binding (Deng et al, 2014) (Fig. 3E).…”

Section: Creative Approaches To Cdk Inhibitionmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

et al. 2015

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Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATPcompetitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATPcompetitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer.

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“…The structure of CDK1 appears to differ from that of CDK2 in terms of the disposition of N- and C-terminal lobes, while it also appears more mobile and malleable ( Brown et al., 2015 ). Inhibitors have been reported that exploit the conformational flexibility of cyclin-free CDK2 to target pockets that stabilize conformations incompatible with cyclin association ( Alexander et al., 2015 , Betzi et al., 2011 , Deng et al., 2014 ). Taken together, these observations suggest that targeting cyclin-free CDK structures might provide a selectivity window between closely related CDK family members.…”

Section: Introductionmentioning

confidence: 99%

Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition

Wood

Korolchuk

Tatum

et al. 2019

Cell Chemical Biology

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SummaryDysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.

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Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor

Cited by 19 publications

References 17 publications

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition

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