Discovery of novel NLRP3 inhibitors enabled by a high-throughput screen

被引：0

作者：

Dorich, Stephane ^{[1
]}

Auger, Anick ^{[1
]}

Wang, Li ^{[2
]}

Burch, Jason ^{[1
]}

Pellerin, Charles ^{[1
]}

Chan, Silas ^{[2
]}

Raymond, Marianne ^{[1
]}

Zhang, Lingling ^{[2
]}

Chefson, Amandine ^{[1
]}

Germain, Marie-Anne ^{[1
]}

Jananji, Silvana ^{[1
]}

Dumais, Valerie ^{[1
]}

Gaudreault, Samuel ^{[1
]}

Caron, Alexandre ^{[1
]}

Dumas-Berube, Emilie ^{[1
]}

Crackower, Michael. A. ^{[2
]}

机构：

[1] Ventus Therapeut Inc, 4800 Rue Levy, St Laurent, PQ H4R 2P1, Canada

[2] Ventus Therapeut US Inc, 100 Beaver St,Suite 201, Waltham, MA 02453 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2025年 / 122卷

关键词：

NLRP3; inhibitors; High-throughput screen (HTS); Scintillation proximity assay (SPA); Brain penetrant; Furan; Pharmacodynamic model; INFLAMMASOME;

D O I：

10.1016/j.bmcl.2025.130184

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

NLRP3 is a key regulator of the innate immune system involved in sensing a variety of pathogen and danger signals. Priming and activation of NLRP3 leads to the release and maturation of pro-inflammatory cytokines, as well as gasdermin D-mediated cell death. Inhibition of dysregulated NLRP3 activity has been associated with promising therapeutic opportunities for a variety of systemic and neurological diseases including atherosclerosis and Parkinson's disease. Herein, we discuss how a high-throughput screen (HTS) allowed us to discover new chemical scaffolds that specifically bind to NLRP3 and inhibit its function in a selective manner. We also describe how an enantiomer of HTS hit 5, compound 11, demonstrated in vivo inhibition of NLRP3.

引用

页数：7

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