High-Throughput Kinase Profiling: A More Efficient Approach toward the Discovery of New Kinase Inhibitors

SummarySelective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that “high-throughput kinase profiling” is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors.

Graphical AbstractFigure optionsDownload high-quality image (143 K)Download as PowerPoint slideHighlights
► High-throughput kinase profiling of inhibitors
► Different type I kinase inhibitor scaffolds and kinase interaction map
► Inhibitors of PIM1, ERK5, ACK1, MPS1/PLK, and Aurora kinases
► Rich source of leads for further medicinal chemistry efforts