Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
Small-molecule protein kinase inhibitors are widely used to elucidate cellular signaling pathways and are promising therapeutic agents. Owing to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments that use these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we used functional assays to profile the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases. Quantitative analysis revealed complex and often unexpected interactions between protein kinases and kinase inhibitors, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can identify multitargeted inhibitors of specific, diverse kinases. The results have implications for drug development and provide a resource for selecting compounds to elucidate kinase function and for interpreting the results of experiments involving kinase inhibitors.
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Theonie
T
Anastassiadis
Sean W
SW
Deacon
Karthik
K
Devarajan
Haiching
H
Ma
Jeffrey R
JR
Peterson
D002384:Catalysis; D015195:Drug Design; D004795:Enzyme Stability; D057166:High-Throughput Screening Assays; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000145:classification; D011494:Protein Kinases / Q000737:chemistry* / Q000145:classification; D015398:Signal Transduction; D013379:Substrate Specificity
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases