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

Autor:	Matico R; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Grauwen K; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium., Chauhan D; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium., Yu X; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Abdiaj I; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Adhikary S; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Adriaensen I; Janssen Research & Development, LLC, In Vivo Sciences (IVS), Turnhoutseweg 30, 2340, Beerse, Belgium., Aranzazu GM; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Alcázar J; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Bassi M; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), Turnhoutseweg 30, 2340, Beerse, Belgium., Brisse E; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium., Cañellas S; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Chaudhuri S; Janssen Research & Development, LLC, Preclinical Sciences and Translational Safety (PSTS), Spring House, PA, 19044, USA., Delgado F; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Diéguez-Vázquez A; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Du Jardin M; Janssen Research & Development, LLC, Discovery Pharmaceutics, Turnhoutseweg 30, 2340, Beerse, Belgium., Eastham V; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Finley M; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Jacobs T; Janssen Research & Development, LLC, Preclinical Sciences and Translational Safety (PSTS), Turnhoutseweg 30, 2340, Beerse, Belgium., Keustermans K; Charles River Laboratories, Turnhoutseweg 30, 2340, Beerse, Belgium., Kuhn R; Janssen Interventional Oncology, Spring House, PA, 19044, USA., Llaveria J; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Leenaerts J; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), Turnhoutseweg 30, 2340, Beerse, Belgium., Linares ML; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Martín ML; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Martín-Pérez R; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium., Martínez C; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Miller R; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Muñoz FM; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Muratore ME; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), Turnhoutseweg 30, 2340, Beerse, Belgium., Nooyens A; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium., Perez-Benito L; Janssen Research & Development, LLC, Therapeutic Discovery, Turnhoutseweg 30, 2340, Beerse, Belgium., Perrier M; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), Turnhoutseweg 30, 2340, Beerse, Belgium., Pietrak B; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Serré J; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium., Sharma S; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Somers M; Janssen Research & Development, LLC, Drug Metabolism and Phamacokinetcs (DMPK), Turnhoutseweg 30, 2340, Beerse, Belgium., Suarez J; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Tresadern G; Janssen Research & Development, LLC, Therapeutic Discovery, Turnhoutseweg 30, 2340, Beerse, Belgium., Trabanco AA; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Van den Bulck D; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Van Gool M; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), Turnhoutseweg 30, 2340, Beerse, Belgium., Van Hauwermeiren F; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium., Varghese T; Janssen Research & Development, LLC, Discovery Technologies and Molecular Pharmacology (DTMP), Spring House, PA, 19044, USA., Vega JA; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), C. Río Jarama, 75, 45007, Toledo, Spain., Youssef SA; Janssen Research & Development, LLC, Preclinical Sciences and Translational Safety (PSTS), Turnhoutseweg 30, 2340, Beerse, Belgium., Edwards MJ; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium., Oehlrich D; Janssen Research & Development, LLC, Global Discovery Chemistry (GDC), Turnhoutseweg 30, 2340, Beerse, Belgium., Van Opdenbosch N; Janssen Interventional Oncology, Turnhoutseweg 30, 2340, Beerse, Belgium. nvanopde@its.jnj.com.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Dec 09. Date of Electronic Publication: 2024 Dec 09.
DOI:	10.1038/s44321-024-00181-4
Abstrakt:	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. Competing Interests: Disclosure and competing interests statement. All authors are (or were) J&J employees when participating in this work and declare no competing interests. (© 2024. The Author(s).)
Databáze:	MEDLINE
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