The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening

• Published in: Bioorganic & medicinal chemistry letters 2024-04, Vol.102, p.129675-129675, Article 129675
• Main Authors: Hartman, George, Humphries, Paul, Hughes, Robert, Ho, Andrew, Montgomery, Rusty, Deshpande, Aditi, Mahanta, Maitriyee, Tronnes, Sarah, Cowdin, Samantha, He, Xu, Liu, Fangchao, Zhang, Lifang, Liu, Chuan, Dou, Dengfeng, Li, Jin, Spasic, Aleksander, Coll, Rebecca, Marleaux, Michael, Hochheiser, Inga V., Geyer, Matthias, Rubin, Paul, Fortney, Kristen, Wilhelmsen, Kevin
• Format: Article
• Language: English
• Subjects: Anti-inflammation; BAL-0028; CADD; DNA-encoded library; IL-18; IL-1β; NLRP3 inflammasome; NLRP3 inhibitor; Pyroptosis; STAND ATPase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2024.129675

[Display omitted] 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. SPR studies showed that compound 3 binds tightly (KD range 104–123 nM) to the NACHT domain of NLRP3. A CADD analysis of the interaction of compound 3 with the NLRP3 NACHT domain proposes a binding site that is distinct from those of ADP and MCC950 and includes specific site interactions. We anticipate that compound 3 (BAL-0028) and other members of this novel indazole class of neutral inhibitors will demonstrate significantly different physical, biochemical, and biological properties compared to NLRP3 inhibitors previously identified.