An insight into the emerging role of cyclin-dependent kinase inhibitors as potential therapeutic agents for the treatment of advanced cancers - 20/09/18
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Graphical abstract |
Highlights |
• | CDKs have been studied comprehensively as targets for antitumor and anticancer therapy. |
• | CDK inhibition is potentially a valuable strategy to achieve the cytotoxicity instead of cell arrest. |
• | Knowledge of ligand-specific recognition may be applied as a key tool for the designing of isoform-specific inhibitors. |
Abstract |
Cancer denotes a pathological manifestation that is characterized by hyperproliferation of cells. It has anticipated that a better understanding of disease pathogenesis and the role of cell-cycle regulators may provide an opportunity to develop an effective cancer therapeutic agents. Specifically, the cyclin-dependent kinases (CDKs) which regulate the transition of cell-cycle through different phases; have been identified as fundamental targets for therapeutic advances. It is an evident from experimental studies that several events leading to tumor growth occur by exacerbation of CDK4/CDK6 in G1-phase of cell division cycle. Additionally, the characteristics of S- and G2/M-phase regulated by CDK1/CDK2 are pivotal events that may lead to abrupt the cell division. Although, previously reported CDK inhibitors have shown remarkable results in pre-clinical studies, but have not yielded appreciable clinical results yet. Therefore, the development of clinically potent CDK inhibitors has remained to be a challenging task. However, continuous efforts has led to the development of some novel CDKs inhibitors that have emerged as a potent strategy for the treatment of advanced cancers. In this article, we have summarized the role of CDKs in cell-cycle regulation and tumorigenesis and recent advances in the development of CDKs inhibitors as a promising therapy for the treatment of advanced cancer. In addition, we have also performed a comparison of crystallographic studies to get valuable insight into the interaction mode differences of inhibitors, binding to CDK isoforms with apparently similar binding sites. The knowledge of ligand-specific recognition towards a particular CDK isoform may be applied as a key tool in future for the designing of isoform-specific inhibitors.
Le texte complet de cet article est disponible en PDF.Abbreviations : CDK, CDK4/6, cdc, CDC25C, Ser/Thr, kDa, Cip/Kip, CKIs, CGB, ATP, cAMP, HTS, pRb, NSCLC, SAR, ECG, FDA, HER2, HR, ER
Keywords : CDK, Mutagenesis, Anticancer, Metastatic cancer, Hyperproliferation
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Vol 107
P. 1326-1341 - novembre 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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