Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2024-04, Vol.102, p.129675-129675, Article 129675

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [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.