[DOT 2018] Combining the Power of Different Profiling Approaches to Better Understand the Activity of Kinase Inhibitor Drugs

[DOT 2018] Combining the Power of Different Profiling Approaches to Better Understand the Activity of Kinase Inhibitor Drugs
File Name/Number:
DOT 2018

Year:
2018

Profiling of inhibitors for eventual therapeutic use is an essential part of drug discovery and development. Evaluating the in vitro potency of kinase inhibitors in a wide panel of enzyme assays is critical, not only to guiding SAR knowledge for improving drug design, but also for assessing selectivity, which has long-reaching consequences for both biological activity of these inhibitors in a more physiologically relevant environment. However, while some selective kinase inhibitors show predictably selective profiles in cell proliferation assays, others do not.Thus the biological context in which a kinase inhibitor functions, and the signaling networks influenced by inhibition of both the desired targetand off-target activities, help to define how that inhibitor will work in a cellular setting and, ultimately, in a therapeutic application. We demonstrate the power of profiling several well-known kinase inhibitors in complementary panel assays, to predict behavior that has implications for clinical activity. The in vitro profiles of selective (trametinib, vemurafenib) and less selective (dasatinib, sorafenib) kinase inhibitors are shown and compared. With careful evaluation of their in vitro enzyme activity profiles in Eurofins’ KinaseProfiler™ panel, cellular response profiles in OncoPanel™, and predictive biomarker identification by univariate genomic analysis, a fuller picture of these inhibitors’ biological activity can be generated, and may be applied to predicting the therapeutic potential of such inhibitors. While, in some cases, clinical response is seen as expected, thiskind of comprehensive analysis opens up the possibility for expanding clinical utility of an asset by potential repurposing for other indications. Collectively, this demonstrates not only the need to understand an inhibitor’s fundamental activity(ies) at its designated target(s), but also the importance of considering cellular context, when assessing its maximum potential clinical utility.