How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?

TLDR

Cyclin‑dependent kinases are key drug targets, yet data on the selectivity of their inhibitors is often lacking. The study evaluates 31 CDK inhibitors for their selectivity against CDKs 1, 2, 4, 5, 7, 9 and their impact on the cell cycle. The authors assessed inhibitor activity and built an online database of commercially available CDK inhibitors. Most CDK inhibitors are pan‑selective, some target other kinases such as Aurora, and the findings guide researchers in choosing appropriate chemical probes.

Abstract

Cyclin-dependent kinases (CDKs) are an important and emerging class of drug targets for which many small-molecule inhibitors have been developed. However, there is often insufficient data available on the selectivity of CDK inhibitors (CDKi) to attribute the effects on the presumed target CDK to these inhibitors. Here, we highlight discrepancies between the kinase selectivity of CDKi and the phenotype exhibited; we evaluated 31 CDKi (claimed to target CDK1–4) for activity toward CDKs 1, 2, 4, 5, 7, 9 and for effects on the cell cycle. Our results suggest that most CDKi should be reclassified as pan-selective and should not be used as a tool. In addition, some compounds did not even inhibit CDKs as their primary cellular targets; for example, NU6140 showed potent inhibition of Aurora kinases. We also established an online database of commercially available CDKi for critical evaluation of their utility as molecular probes. Our results should help researchers select the most relevant chemical tools for their specific applications.