Abstract 1242: A broad activity screen in support of a chemogenomic map for kinase signaling research and drug discovery

Abstract

Abstract Since protein kinases play a fundamental role in cell signaling, especially as components of critical growth and differentiation pathways linked to cancer, kinase inhibitors have been commercialized as both therapeutics and research tools. This has been enabled to some degree by the chemical tractability of protein kinase ATP binding pockets, the automation of activity measurements, and the correlation of in vitro, cellular, and in vivo activities. 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 structure and activity across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using “gold standard” radiometric assays for inhibitory activity toward 234 kinases, which represent all branches of the kinome tree. We screened 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important from a therapeutic target as well as a signal transduction biology perspective. We performed hierarchical clustering of these benchmark kinase inhibitors based upon their kinome activity profiles and illustrate how they relate to chemical structure similarities; this provides new insights into inhibitor specificity and potential applications for probing new targets. Additionally, we developed a selectivity score for each kinase which we believe reflects general binding site accessibility to small molecules. Knowledge of such scoring indices can play an important role in therapeutic target selection and drug discovery strategies. Using this broad set of data, we provide a framework for assessing polypharmacology. Examples will be shown to demonstrate that we not only identify likely off-target inhibitor activities but also potential new uses for known small molecules. Moreover we demonstrate how activity data can be used to help explain the effects of small molecules observed in phenotypic screening. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1242. doi:1538-7445.AM2012-1242