An insight into the emerging role of cyclin-dependent kinase inhibitors as potential therapeutic agents for the treatment of advanced cancers

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.

Keywords: Anticancer; CDK; Hyperproliferation; Metastatic cancer; Mutagenesis.