KIN-8194 selectively targets HCK and BTK in vitro in MYD88-mutated WM and ABC DLBCL cells. (A) Chemical structure of KIN-8194. (B) KINOMEscan kinase selectivity profile for KIN-8194. KIN-8194 was profiled at a concentration of 1.0 μM against a diverse panel of 464 kinases by using DiscoverX. Kinases that exhibited a score of 10% or below are marked in red circles. (C) KiNativ cellular target engagement profile for KIN-8194. Kinases engaged >50% with 1.0 µM KIN-8194 treatment in TMD-8 cells are labeled. Kinases demonstrating >90% inhibition in KiNativ profiling (as shown in supplemental Table 2) were subjected to enzymatic IC50 determination as shown here. (D) Activated kinases enriched by pulldown assay using Desthiobiotin-ATP Probe after BCWM.1 and TMD-8 live cells pretreated with KIN-8194 or ibrutinib at indicated concentrations for 90 minutes and the ATP-binding HCK and BTK were resolved by western blotting. IB, ibrutinib.