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

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.