吲唑
炎症体
化学
药物发现
计算生物学
吡喃结构域
上睑下垂
半胱氨酸蛋白酶1
细胞内
铅化合物
立体化学
细胞生物学
体外
生物化学
受体
生物
作者
George D. Hartman,Paul S. Humphries,Robert Hughes,Ambrose Chung–Wai Ho,Rusty L. Montgomery,Aditi Deshpande,Maitriyee Mahanta,Sarah U. Tronnes,Samantha Cowdin,Xingjian He,Fangchao Liu,Lifang Zhang,Chuan Liu,Dengfeng Dou,Jin Li,Aleksander Spasic,Rebecca C. Coll,Michael Marleaux,Inga V. Hochheiser,Matthias Geyer,Paul Rubin,Kristen Fortney,Kevin Wilhelmsen
标识
DOI:10.1016/j.bmcl.2024.129675
摘要
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.
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