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Kinase Inhibitors: Not Just for Kinases Anymore

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Susan L. McGovern^† and Brian K. Shoichet*^‡

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, and Department of Pharmaceutical Chemistry, Genentech Hall, 600 16th Street, University of CaliforniaSan Francisco, San Francisco, California 94143

J. Med. Chem., 2003, 46 (8), pp 1478–1483

DOI: 10.1021/jm020427b

Publication Date (Web): March 12, 2003

Abstract

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.

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Published In Issue April 10, 2003
Received September 26, 2002

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Article

Kinase Inhibitors: Not Just for Kinases Anymore

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Identification and Prediction of Promiscuous Aggregating Inhibitors among Known Drugs

A Specific Mechanism of Nonspecific Inhibition

A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening

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