A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery

• DOI: 10.1042/bj20121418
• Publication Date: 2013-02-13T09:17:07Z
• Authors: Yinghong Gao; Stephen P. Davies; Martin Augustin; Anna Woodward; Umesh A. Patel; Robert Kovelman; Kevin J. Harvey
• Keywords: 0303 health sciences; MAP Kinase Kinase 4; Drug Evaluation, Preclinical; Intracellular Signaling Peptides and Proteins; Reproducibility of Results; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Recombinant Proteins; 3. Good health; ErbB Receptors; Small Molecule Libraries; Structure-Activity Relationship; 03 medical and health sciences; Receptors, Vascular Endothelial Growth Factor; Aurora Kinases; Drug Design; Drug Discovery; Cluster Analysis; Humans; Syk Kinase; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction

Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.