Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome

Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome

Abstract The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. P...

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Main Authors: Rosalie Matico, Karolien Grauwen, Dhruv Chauhan, Xiaodi Yu, Irini Abdiaj, Suraj Adhikary, Ine Adriaensen, Garcia Molina Aranzazu, Jesus Alcázar, Michela Bassi, Ellen Brisse, Santiago Cañellas, Shubhra Chaudhuri, Francisca Delgado, Alejandro Diéguez-Vázquez, Marc Du Jardin, Victoria Eastham, Michael Finley, Tom Jacobs, Ken Keustermans, Robert Kuhn, Josep Llaveria, Jos Leenaerts, Maria Lourdes Linares, Maria Luz Martín, Rosa Martín-Pérez, Carlos Martínez, Robyn Miller, Frances M Muñoz, Michael E Muratore, Amber Nooyens, Laura Perez-Benito, Mathieu Perrier, Beth Pietrak, Jef Serré, Sujata Sharma, Marijke Somers, Javier Suarez, Gary Tresadern, Andres A Trabanco, Dries Van den Bulck, Michiel Van Gool, Filip Van Hauwermeiren, Teena Varghese, Juan Antonio Vega, Sameh A Youssef, Matthew J Edwards, Daniel Oehlrich, Nina Van Opdenbosch
Format: Article
Language:English
Published: Springer Nature 2024-12-01
Series:EMBO Molecular Medicine
Subjects:
Novel Inhibitor
NLRP3
IL-1β
Inflammasome
Clinical Candidate
Online Access:https://doi.org/10.1038/s44321-024-00181-4
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Summary:Abstract The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3. In this study, we present the identification of a novel chemical class exhibiting selective and potent inhibition of the NLRP3 inflammasome. Through a comprehensive structure–activity relationship (SAR) campaign, we optimized the lead molecule, compound A, for in vivo applications. Extensive in vitro and in vivo characterization of compound A confirmed the high selectivity and potency positioning compound A as a promising clinical candidate for diseases associated with aberrant NLRP3 activity. This research contributes to the ongoing efforts in developing targeted therapies for conditions involving NLRP3-mediated inflammation, opening avenues for further preclinical and clinical investigations.
ISSN:1757-4684

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