2. Academic Validation
  3. Discovery of novel NLRP3 inhibitors enabled by a high-throughput screen

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

Affiliations

  • 1 Ventus Therapeutics, Inc., 4800 rue Levy, Saint-Laurent, H4R 2P1, QC, Canada. Electronic address: sdorich@ventustx.com.
  • 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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