Transformation of in vitro tools for kinase profiling: keeping an eye over the off-target liabilities.

INTRODUCTION: Over the past decade, there has been an increased number of FDA approved small molecule kinase inhibitors for the treatment of cancer. This is due, in part, to an increased understanding of the fundamental aspects of kinase biology, coupled with advances in the methods used to study the inhibitory effects of small molecules on kinase activity. Underlying the development of these inhibitors are profiling methods that are used to assess the effect of potential compounds against their desired and undesired targets. The advancement of kinase profiling has stemmed from the development of basic assay technology that allows compounds to be tested against ever larger panels of kinases in a robust, cost-effective manner. Methods have also been developed that rapidly assess compound activity against specific activation states of kinases. There has also been a development of newer methods that move beyond traditional biochemical formats, which take a 'whole cell' approach to compound profiling. AREAS COVERED: This review provides an overview of traditional biochemical-based kinase profiling as well as an introduction to advances that have been made by moving compound profiling into a cell-based format. EXPERT OPINION: While central to the appropriate prioritization and optimization of compounds during the hit to lead phase of early-stage pharmaceutical development, every compound profiling format must be critically assessed so that one can make informed decisions through an understanding of their strengths and limitations. These decisions will ultimately be balanced against cost, complexity and its biological relevance.