2. Academic Validation
  3. Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action

Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action

  • J Exp Med. 2025 Nov 3;222(11):e20242403. doi: 10.1084/jem.20242403.
Kevin Wilhelmsen 1,  Aditi Deshpande 1,  Sarah Tronnes 1,  Maitriyee Mahanta 1,  Matthew Banicki 1,  Mary Cochran 1,  Samantha Cowdin 1,  Kristen Fortney 1,  George Hartman 1,  Robert E Hughes 1,  Rusty Montgomery 1,  Claudia P Portillo 1,  Paul Rubin 1,  Taiz Salazar 1,  Yan Wang 1,  Shijun Yan 1,  Barry A Morgan 2,  Assem Duisembekova 3,  Romane Riou 3,  Michael Marleaux 4,  Inga V Hochheiser 4,  Hannes Buthmann 4,  Dominic Ferber 4,  Jane Torp 4,  Wei Wang 5,  Melanie Cranston 5,  Chloe M McKee 5,  Thea J Mawhinney 5,  Emma C McKay 5,  Fehime K Eroglu 6 7,  Jasmin Kümmerle-Deschner 7,  Alexander N R Weber 6 8,  Bénédicte F Py 3,  Matthias Geyer 4,  Rebecca C Coll 5
Affiliations

Affiliations

  • 1 BioAge Labs , Emeryville, CA, USA.
  • 2 HitGen Pharmaceuticals Inc. , Houston, TX, USA.
  • 3 CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon , Lyon, France.
  • 4 Institute of Structural Biology, University of Bonn , Bonn, Germany.
  • 5 Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast , Belfast, UK.
  • 6 Department of Innate Immunity, Institute of Immunology, Tübingen, Germany.
  • 7 Department of Pediatrics I, Pediatric Rheumatology and Autoinflammation Reference Center, University Hospital Tübingen, Tübingen, Germany.
  • 8 Cluster of Excellence 2180 "Image-guided and Functionally Instructed Tumor Therapies" and Cluster of Excellence 2124 "Controlling Microbes to Fight Infection", University of Tübingen , Tübingen, Germany.
PMID: 40892070 DOI: 10.1084/jem.20242403
Abstract

The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and Pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously performed a DNA-encoded library screen to identify novel NLRP3-binding molecules. Herein we describe the characterization of BAL-0028 as a potent and specific inhibitor of NLRP3 signaling. Notably, BAL-0028 is a poor inhibitor of mouse NLRP3 but inhibits human and primate NLRP3 with nanomolar potency. Using cellular and biochemical analyses, we demonstrate that BAL-0028 binds to the NLRP3 NACHT domain at a site that is distinct from the MCC950-binding pocket. Using humanized NLRP3 mice, we show that a derivative of BAL-0028, BAL-0598, inhibits NLRP3 activation in vivo in a peritonitis model. Finally, we demonstrate that both BAL-0028 and BAL-0598 inhibit select hyperactive NLRP3 mutations associated with autoinflammatory diseases more potently than MCC950. BAL-0028 and BAL-0598 thus represent a new modality for NLRP3 inhibition in inflammatory diseases.

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