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

  • Bioorg Med Chem Lett. 2025 Jul 1:122:130184. doi: 10.1016/j.bmcl.2025.130184.
Stéphane Dorich  1 ,  Anick Auger  2 ,  Li Wang  3 ,  Jason Burch  2 ,  Charles Pellerin  2 ,  Silas Chan  3 ,  Marianne Raymond  2 ,  Lingling Zhang  3 ,  Amandine Chefson  2 ,  Marie-Anne Germain  2 ,  Silvana Jananji  2 ,  Valérie Dumais  2 ,  Samuel Gaudreault  2 ,  Alexandre Caron  2 ,  Émilie Dumas-Bérubé  2 ,  Michael A Crackower  3
Affiliations
  • 1. Ventus Therapeutics, Inc., 4800 rue Levy, Saint-Laurent, H4R 2P1, QC, Canada. Electronic address: [email protected].
  • 2. Ventus Therapeutics, Inc., 4800 rue Levy, Saint-Laurent, H4R 2P1, QC, Canada.
  • 3. Ventus Therapeutics U.S., Inc., 100 Beaver St., Suite 201, Waltham, MA 02453, USA.
PMID: 40089037 DOI: 10.1016/j.bmcl.2025.130184
Abstract

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.

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