George Hartman, Paul Humphries, Robert Hughes, Andrew Ho, Rusty Montgomery, Aditi Deshpande, Maitriyee Mahanta, Sarah Tronnes, Samantha Cowdin, Xu He, Fangchao Liu, Lifang Zhang, Chuan Liu, Dengfeng Dou, Jin Li, Aleksander Spasic, Rebecca Coll, Michael Marleaux, Inga V Hochheiser, Matthias Geyer, Paul Rubin, Kristen Fortney, Kevin Wilhelmsen
NLRP3 is an intracellular sensor protein that detects a broad range of danger signals and environmental insults. Its activation results in a protective pro-inflammatory response designed to impair pathogens and repair tissue damage via the formation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent secretory release of the pro-inflammatory cytokines IL-1β and IL-18 as well as to gasdermin d-mediated pyroptotic cell death. Herein, we describe the discovery of a novel indazole series of high affinity, reversible inhibitors of NLRP3 activation through screening of DNA-encoded libraries and the potent lead compound 3 (BAL-0028, IC50 = 25 nM) that was identified directly from the screen...
February 26, 2024: Bioorganic & Medicinal Chemistry Letters