Kinase Inhibitors: Not Just for Kinases Anymore

Kinase inhibitors are widely employed as biological reagents and as leads for drug design.
Their use is often complicated by their lack of specificity. Although binding conserved ATP
sites accounts for some of their nonspecificity, some compounds inhibit proteins not known to
bind ATP. It has been found that promiscuous hits from high-throughput screening may act
as aggregates. To explore whether this mechanism might explain the action of widely used
nonspecific kinase inhibitors, 15 such compounds were studied. Eight of these, rottlerin,
quercetin, K-252c, bisindolylmaleimide I, bisindolylmaleimide IX, U0126, indirubin, and indigo,
inhibited three diverse non-kinase enzymes. Inhibition was time-dependent and sensitive to
enzyme concentration; by light scattering, the compounds formed particles of 100−1000 nm
diameter. These observations suggest that these eight kinase inhibitors, at least at micromolar
concentrations, are promiscuous and act as aggregates. Results obtained from the use of these
compounds at micromolar or higher concentrations against individual enzymes should be
interpreted cautiously.