Article
Author: Jiang, Tao ; Glatthar, Ralf ; André, Cédric ; Boulay, Thomas ; Pei, Wei ; Mutnick, Daniel ; Han, Dong ; Betschart, Claudia ; Hemmig, Rene ; Michellys, Pierre-Yves ; Feifel, Roland ; Maginnis, Jillian ; Ruzzante, Giulia ; Deane, Jonathan ; Syka, Peter ; Zhang, Guobao ; Hawtin, Stuart ; Zipfel, Géraldine ; Alper, Phil ; Junt, Tobias ; Faller, Michael ; Knoepfel, Thomas ; Cheng, Dai ; Zink, Florence ; Zhang, Yi
Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren's syndrome and mixed connective tissue disease.