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

来自 万方医学

阅读量：

146

作者：

T Anastassiadis，SW Deacon，K Devarajan，H Ma，JR Peterson

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摘要：

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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关键词：

Humans Protein Kinases Protein Kinase Inhibitors Signal Transduction Enzyme Stability Protein Binding Substrate Specificity Drug Design High-Throughput Screening Assays Catalysis

DOI：

10.1038/nbt.2017

被引量：

654

年份：

2011

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来源期刊

Nature Biotechnology
2011/11/01

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2014
被引量：155

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