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Peer-Reviewed Publication
J Exp Med2025;222(11)November 3, 2025Journal Article

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

Kevin Wilhelmsen1, Aditi Deshpande1, Sarah Tronnes1, Maitriyee Mahanta1, Matthew Banicki1, Mary Cochran1, Samantha Cowdin1, Kristen Fortney1, George Hartman1, Robert E Hughes1, Rusty Montgomery1, Claudia P Portillo1, Paul Rubin1, Taiz Salazar1, Yan Wang1, Shijun Yan1, Barry A Morgan2, Assem Duisembekova3, Romane Riou3, Michael Marleaux4, Inga V Hochheiser4, Hannes Buthmann4, Dominic Ferber4, Jane Torp4, Wei Wang5, Melanie Cranston5, Chloe M McKee5, Thea J Mawhinney5, Emma C McKay5, Fehime K Eroglu6,7, Jasmin Kümmerle-Deschner7, Alexander N R Weber6,8, Bénédicte F Py3, Matthias Geyer4, Rebecca C Coll5
1BioAge Labs , Emeryville, CA, USA.
2HitGen Pharmaceuticals Inc. , Houston, TX, USA.
3CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon , Lyon, France.
4Institute of Structural Biology, University of Bonn , Bonn, Germany.
5Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast , Belfast, UK.
6Department of Innate Immunity, Institute of Immunology, Tübingen, Germany.
7Department of Pediatrics I, Pediatric Rheumatology and Autoinflammation Reference Center, University Hospital Tübingen, Tübingen, Germany.
8Cluster 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.
PubMed PMC DOI PDF

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 BA…

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