Discovery of Tyk2 inhibitors via the virtual site-directed fragment-based drug design

In this study, we synthesized compound 12 with potent Tyk2 inhibitory activity from FBDD study and carried out a cell-based assay for Tyk2/ STAT3signaling activation upon IFNα5 stimulation. Compound 12 completely suppressed the IFNα5-mediated Tyk2/ STAT3signaling pathway as well as the basal levels of pSTAT3. Stimulation with IFNα/β leads to the tyrosine phosphorylationof the JAK1 and Tyk2 receptor-associated kinases with subsequent STATs activation, transmitting signals from the cell surface receptorto the nucleus. In conclusion, the potency of compound 12 to interrupt the signal transmission of Tyk2/ STAT3appeared to be equivalent or superior to that of the reference compound.