Fig. 1 BMS-986165 binds to the pseudokinase domain of TYK2 and inhibits receptor-mediated TYK2 activation and downstream phosphorylation events in human.

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Fig. 1 BMS-986165 binds to the pseudokinase domain of TYK2 and inhibits receptor-mediated TYK2 activation and downstream phosphorylation events in human immune cells. BMS-986165 binds to the pseudokinase domain of TYK2 and inhibits receptor-mediated TYK2 activation and downstream phosphorylation events in human immune cells. (A) Domain structure of TYK2. SH2, Src homology 2; Ferm, F for 4.1 protein, E for ezrin, R for radixin and M for moesin; MFI, median fluorescence intensity. (B) Chemical structure of BMS-986165. (C) Dependence of Ki,app of BMS-986165 on fluorescent probe concentration for binding to the TYK2 pseudokinase domain in a homogeneous time resolved fluorescence (HTRF) assay. (D) Effect of BMS-986165 on IFNα-induced phosphorylation of TYK2 at Tyr1054/Tyr1055 in kit225 T cells. Loading was normalized by coanalysis of tubulin levels. Effect of BMS-986165 on phosphorylation of STAT1 in CD3+ T cells (E) and CD19+ B cells (F) upon stimulation of human PBMCs with IFNα. The data are representative of two independent experiments with different donors and with two independent replicates within this experiment. (G) Effect of BMS-986165 on the phosphorylation of STAT5 in CD3+ T cells in human PBMCs stimulated with IL-2. The data are representative of three independent experiments with two independent replicates within this experiment. James R. Burke et al., Sci Transl Med 2019;11:eaaw1736 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works