BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA.
BioAge Labs, 1445 S. 50(th) St. Richmond, CA 94804, USA.
Bioorg Med Chem Lett. 2024 Apr 1;102:129675. doi: 10.1016/j.bmcl.2024.129675. Epub 2024 Feb 28.
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 (K 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.
NLRP3 是一种细胞内传感器蛋白，可检测广泛的危险信号和环境损伤。其激活会导致保护性的促炎反应，旨在通过形成 NLRP3 炎性小体来削弱病原体并修复组织损伤。NLRP3 炎性小体的组装导致半胱天冬酶 1 依赖性促炎细胞因子 IL-1β 和 IL-18 的分泌释放，以及气液蛋白 d 介导的细胞焦亡。在此，我们通过 DNA 编码文库筛选描述了一种新型吲唑系列高亲和力、可逆的 NLRP3 激活抑制剂的发现，以及直接从筛选中鉴定出的强效先导化合物 3（BAL-0028，IC50=25 nM）。SPR 研究表明，化合物 3 与 NLRP3 的 NACHT 结构域紧密结合（K 范围为 104-123 nM）。化合物 3 与 NLRP3 NACHT 结构域相互作用的 CADD 分析提出了一个与 ADP 和 MCC950 不同的结合位点，包括特定的位点相互作用。我们预计化合物 3（BAL-0028）和该新型吲唑类中性抑制剂的其他成员将表现出与先前鉴定的 NLRP3 抑制剂明显不同的物理、生化和生物学特性。
