Inhibitors of cell cycle kinases: recent advances and future prospects as cancer therapeutics

Abstract

The cell cycle is a tightly regulated series of events that governs cell replication and division. Deregulation of cell cycle kinases, e.g., cyclin-dependent kinases (CDKs), can initiate a hyper-proliferative cell phenotype and cause genomic instability, thus facilitating malignant transformation. Pharmacological agents targeting CDKs have been developed as potential anti-cancer agents for over 20 years, evolving from early pan-CDK inhibitors to second-generation inhibitors with much greater specificity and selectivity. Despite these advances in drug design and highly successful preclinical investigations, CDK inhibitors have yet to achieve their expected efficacy in clinical trials. In addition, inhibitors of other cell cycle kinases are currently progressing through clinical trials. Recent biochemical and genetic studies might be used to improve the effectiveness of cell cycle kinase inhibitors as anti-cancer agents through better drug design, therapeutic combinations, and patient selection.