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

摘要

In this study, we synthesized compound 12 with potent Tyk2 inhibitory activity from FBDD study and carried out a cell- based assay for Tyk2/STAT3 signaling activation upon IFN alpha 5 stimulation. Compound 12 completely suppressed the IFN alpha 5-mediated Tyk2/STAT3 signaling pathway as well as the basal levels of pSTAT3. Stimulation with IFN alpha/beta leads to the tyrosine phosphorylation of the JAK1 and Tyk2 receptor-associated kinases with subsequent STATs activation, transmitting signals from the cell surface receptor to the nucleus. In conclusion, the potency of compound 12 to interrupt the signal transmission of Tyk2/STAT3 appeared to be equivalent or superior to that of the reference compound. (C) 2015 Elsevier Ltd. All rights reserved.