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

First Author  Matico R Year  2025
Journal  EMBO Mol Med Volume  17
Issue  1 Pages  54-84
PubMed ID  39653810 Mgi Jnum  J:371272
Mgi Id  MGI:7854222 Doi  10.1038/s44321-024-00181-4
Citation  Matico R, et al. (2025) Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome. EMBO Mol Med 17(1):54-84
abstractText  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.
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