Kinases are very attractive small molecular drug targets; over 40 kinase inhibitors are already approved by the FDA. One critical aspect of kinase inhibitors is the selectivity profile among kinases – there are over 700 kinases (protein, lipid, even carbohydrate), all have very similar small molecule binding pocket - ATP binding pocket. As a result, small molecule kinase inhibitors usually hit multiple kinase inhibitors, with very few exceptions of allosteric inhibitors. To address the issue, a set of tools were developed at EMD Serono to analyze, visualize and evaluate kinase selectivity profiles. Among them, there are a web base application to generate kinase inhibitory plots on kinome, a heatmap application to analyze multiple compounds kinase inhibitory profile for hit selection, as well as a set of Spotfire templates to address difference between kinase assays. By profiling kinase selectivity of approved small molecule kinase inhibitors, we identify a few metrics to better assess kinase selectivity and their effect on clinical outcomes. In addition, we also found that selectivity is not as important for oncology indications as initially thought, promiscuous inhibitors actually have a higher chance to make it to the market. Beside selectivity profile analysis, we also compared assay panel results from different CROs for the same kinases. While for majority of kinases, results are agreed with each other among suppliers, there are also a quite a few exceptions. All these tools and results not only provide deep insight into kinase profiles, but also help project teams to evaluate kinase drug candidates and make critical decisions.

Kinase inhibitor selectivity data analysis

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.