CDK2/cyclinA inhibitors: Targeting the cyclinA recruitment site with small molecules derived from peptide leads

Castanedo, Georgette; Wang, Shumei; Tsui, Vickie; Wong, Mengling; Nicholas, John B.; Wickramasinghe, Dineli; Marsters, James C.; Sutherlin, Daniel P.

doi:10.1016/j.bmcl.2005.12.004

Cited by 33 publications

(30 citation statements)

References 14 publications

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“…Substrate or protein partner binding sites can be targeted [22,31], although these often involve protein-protein interactions over large surface areas which are difficult to inhibit with small molecules [80]. Some kinases also contain allosteric sites, pockets remote from the ATP binding site into which inhibitors can bind, altering the overall conformation of the catalytic domain and inhibiting the enzyme (Fig.…”

Section: Protein Kinase Structure and Selective Inhibitionmentioning

confidence: 99%

Measuring and interpreting the selectivity of protein kinase inhibitors

2009

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Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer. Achieving inhibitor selectivity for particular protein kinases often remains a significant challenge in the development of new small molecules as drugs or as tools for chemical biology research. This review summarises the methodologies available for measuring kinase inhibitor selectivity, both in vitro and in cells. The interpretation of kinase inhibitor selectivity data is discussed, particularly with reference to the structural biology of the protein targets. Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors.

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Section: Protein Kinase Structure and Selective Inhibitionmentioning

confidence: 99%

Measuring and interpreting the selectivity of protein kinase inhibitors

2009

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“…Those H bond contacts strengthen the p27-cyclin A interaction [39]; identically, all the peptidomimetics also impersonate the crucial interactions. However, the experimental study also has provided the evidence for the fact that LFG containing synthetic lower molecular weight leads exhibited greater or equivalent selectivity than natural octapeptide inhibitor [9].…”

Section: Molecular Docking and Atomic Interactionmentioning

confidence: 98%

“…The experimental reports suggested that leucine, phenylalanine, and glycine motif containing pentapeptide (RKLFG) potentially inhibited the CDK2/cyclin A complex activation [9,1]. The docking analysis showed that the binding pocket of cyclin groove mainly concerned with the hydrophobic amino acid residues and LFG motif region plays central role in CBG site recognition and specific interaction (Fig.…”

Section: Principle and Structural Designing Of Peptidomimeticsmentioning

confidence: 99%

“…1). The suitable modification on the side chains of the LFG residues improves the hydrophobic contacts in the binding site and could enhance the potency when compared to the truncated peptide leads [9]. Thus, LFG motif was taken as template, and Nterminal caped with suitable unnatural amino acid derivatives converts them into effective peptidomimetics.…”

Section: Principle and Structural Designing Of Peptidomimeticsmentioning

confidence: 99%

“…Disrupting the conserved cyclin-binding groove (CBG) of cyclin A is one of the possible ways to specifically inactivate the G1 to S phase transition of CDK2 complex [2]. Designing of peptide-based inhibitors that target the CBG site is a revolutionary approach to block the malignant cellular proliferation [9,26,27].…”

Section: Introductionmentioning

confidence: 99%

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Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27KIP1-derived peptidomimetic inhibitors

Arumugasamy

Tripathi

Shanmugam³

et al. 2014

J Chem Biol

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Functionally activated cyclin-dependent kinase 2 (CDK2)/cyclin A complex has been validated as an interesting therapeutic target to develop the efficient antineoplastic drug based on the cell cycle arrest. Cyclin A binds to CDK2 and activates the kinases as well as recruits the substrate and inhibitors using a hydrophobic cyclin-binding groove (CBG). Blocking the cyclin substrate recruitment on CBG is an alternative approach to override the specificity hurdle of the currently available ATP site targeting CDK2 inhibitors. Greater understanding of the interaction of CDK2/cyclin A complex with p27 (negative regulator) reveals that the LeuPhe-Gly (LFG) motif region of p27 binds with the CBG site of cyclin A to arrest the malignant cell proliferation that induces apoptosis. In the present study, Replacement with Partial Ligand Alternatives through Computational Enrichment (REPLACE) drug design strategies have been applied to acquire LFG peptide-derived peptidomimetics library. The peptidomimetics function is equivalent with respect to substrate p27 protein fashion but does not act as an ATP antagonist. The combined approach of molecular docking, molecular dynamics (MD), and molecular electrostatic potential and ADME/T prediction were carried out to evaluate the peptidomimetics. Resultant interaction and electrostatic potential maps suggested that smaller substituent is desirable at the position of phenyl ring to interact with Trp217, Arg250, and Gln254 residues in the active site. The best docked poses were refined by the MD simulations which resulted in conformational changes. After equilibration, the structure of the peptidomimetic and receptor complex was stable. The results revealed that the various substrate protein-derived peptidomimetics could serve as perfect leads against CDK2 protein.

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