PKIS Deep Dive Yields a Chemical Starting Point for Dark Kinases and a Cell Active BRSK2 Inhibitor

The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011–2015 and by SGC-UNC from 2015–2017. Screening this library of well-annotated, published kinase inhibitors has yielded a plethora of data in diverse therapeutic and scientific areas, funded applications, publications, and provided impactful pre-clinical results. Based on kinome-wide screening results, we report a thorough investigation of one PKIS compound, GW296115, as an inhibitor of several members of the Illuminating the Druggable Genome (IDG) list of understudied dark kinases. Specifically, GW296115 validates as a potent lead chemical tool that inhibits six IDG kinases with IC 50 values less than 100nM. Focused studies establish that GW296115 is cell active, and directly engages BRSK2. Further evaluation showed that GW296115 downregulates BRSK2-driven phosphorylation and downstream signaling. Summary Statement GW296115 inhibits understudied kinases, including BRSK2, with IC 50 values less than 100nM.