Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity

T Anastassiadis, SW Deacon, K Devarajan, H Ma… - Nature …, 2011 - nature.com
T Anastassiadis, SW Deacon, K Devarajan, H Ma, JR Peterson
Nature biotechnology, 2011nature.com
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 …
Abstract
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.
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