Abstract
Cyclin-dependent kinase 5 (CDK5) is the serine/threonine-directed kinase mainly found in the brain and plays a significant role in developing the central nervous system. Recent evidence suggests that CDK5 is activated by specific cyclins regulating its expression and activity. P35 and p39 activate CDK5, and their proteolytic degradation produces p25 and p29, which are stable products involved in the hyperphosphorylation of tau protein, a significant hallmark of various neurological diseases. Numerous high-affinity inhibitors of CDK5 have been designed, and some are marketed drugs. Roscovitine, like other drugs, is being used to minimize neurological symptoms. Here, we performed an extensive literature analysis to highlight the role of CDK5 in neurons, synaptic plasticity, DNA damage repair, cell cycle, etc. We have investigated the structural features of CDK5, and their binding mode with the designed inhibitors is discussed in detail to develop attractive strategies in the therapeutic targeting of CDK5 for neurodegenerative diseases. This review provides deeper mechanistic insights into the therapeutic potential of CDK5 inhibitors and their implications in the clinical management of neurodegenerative diseases.
•CDK5 is a Ser/Thr kinase that plays significant roles in neuronal differentiation and tau hyperphosphorylation.•This review deals with the structure, function and role of CDK5 in developing neurodegenerative diseases.•Structural features of CDK5 and its interactions with potential inhibitors are illustrated.•We discuss recently developed CDK5 inhibitors and their mechanism of actions.