Cyclin-dependent kinase inhibitors: cancer killers to neuronal guardians.

ABSTRACT

The development of small molecule kinase inhibitors as potential cancer therapeutics is an area of intense interest, and a subset of these agents target cyclin-dependent kinase (CDK) activity. Ten distinct CDKs (1-9, 11), when paired with their cyclin activators, are integral to such diverse processes as cell cycle control, neuronal development, and transcriptional regulation. Mutation and/or aberrant expression of certain CDKs and their regulatory counterparts are associated with uncontrolled proliferation and tumorigenesis. As such, CDK selective inhibitors (CDKIs) that attenuate or prevent tumor growth have been developed. Recently, interest in the therapeutic potential of CDKIs has expanded to include neurodegenerative diseases, where dysregulated CDK activity has been linked to the pathogenesis of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke. Specifically, aberrant activation of cell cycle CDKs or CDK5 is associated with apoptosis and neuronal dysfunction in response to various neuronal stressors. To date, CDKIs have shown promise as neuroprotective agents in the research laboratory and, in the future, may prove useful in the neurology clinic.