Abstract
The master regulators, cyclin dependant kinases (CDKs), are the actual driving forces behind the progression of cell cycle in eukaryotic cells. The activity level of these kinases is maintained and controlled by the periodic synthesis and degradation of positive regulators, cyclins, negative regulators, cyclin kinase inhibitors (CKIs) and other reversible phosphorylation events. CDK/cyclin complexes regulate each phase of the cell cycle and the breakdown of this regulation in any phase results in uncontrolled growth and thus tumor formation. If not all, most of the cancers show direct or indirect deregulation of these kinases, therefore targeting CDKs is an important mode to develop new anticancer therapeutics. Promising preclinical data of many compounds led to the entry of a few of these compounds into clinical trials where excellent results have maintained the high hopes and the recent discovery of one of these compounds as a commercially available drug has further enriched this area of research. So far much has been said about these essential targets but there is a need to discuss their role, mechanism, avenues and progress timely for further understanding of CDKs as anticancer drug targets and to learn how best new CDK inhibitors could be put into clinically developed agents.
Highlights
Progression of cells through four sequential phases of cell cycle namely, G1, S, G2 and M phase is tightly controlled and monitored by checkpoints, the enzymatic complexes known as cyclin dependant kinases (CDKs)
Each phase of cell cycle is regulated by a unique set of CDKs which are in turn positively regulated by onset of particular cyclin partners
In contrast to CDK protein levels, which remain stable throughout the cell cycle, the levels of activating cyclins differ in different stages of cycle [2]
Summary
Progression of cells through four sequential phases of cell cycle namely, G1, S, G2 and M phase is tightly controlled and monitored by checkpoints, the enzymatic complexes known as CDKs. CDKs are sub-divided into two main categories including 11 classical CDKs (CDK1-11) and two newly proposed family members (CDK 12-13) Besides this there are some additional proteins whose names are either based on the presence of a cyclin-binding element such as (PFTAIRE and PCTAIRE proteins) or sequence relationship with the original CDKs, such as CDC2L (CDC2-like kinases) and CCRK (Cell cycle-related kinases) [1]. The phosphorylation of Thr 14/Tyr 15 residues by proteins like Wee and Myt kinases negatively regulate the CDKs. In addition there are some endogenous protein inhibitors of CDK activity known as cyclin kinase inhibitors (CKIs) including the INK4 group such as p16Ink4a, P15Ink4b, P18 Ink4c and P19 Ink4d and the CIP/ KIP class such as p21CIP1/waf, p27kip and p57kip family members (Figure 1). J Cancer Sci Ther 6: 488-496. doi:10.4172/19485956.1000313
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