Novel Aryl Sulfonamide Derivatives as NLRP3 Inflammasome Inhibitors for the Potential Treatment of Cancer.

Autor:	Albanese V; Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy., Missiroli S; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy.; Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), via Fossato di Mortara 70, 44121 Ferrara, Italy., Perrone M; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy.; Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), via Fossato di Mortara 70, 44121 Ferrara, Italy., Fabbri M; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy., Boncompagni C; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy.; Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), via Fossato di Mortara 70, 44121 Ferrara, Italy., Pacifico S; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy., De Ventura T; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy., Ciancetta A; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy., Dondio G; Aphad Srl, Via della Resistenza 65, 20090 Buccinasco, Italy., Kricek F; NBS-C Bioscience & Consulting GmbH, 1230 Vienna, Austria., Pinton P; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy.; Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), via Fossato di Mortara 70, 44121 Ferrara, Italy., Guerrini R; Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), via Fossato di Mortara 70, 44121 Ferrara, Italy.; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy., Preti D; Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy., Giorgi C; Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy.; Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), via Fossato di Mortara 70, 44121 Ferrara, Italy.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Apr 13; Vol. 66 (7), pp. 5223-5241. Date of Electronic Publication: 2023 Mar 27.
DOI:	10.1021/acs.jmedchem.3c00175
Abstrakt:	The NLRP3 inflammasome is a critical component of innate immunity that senses diverse pathogen- and host-derived molecules. However, its aberrant activation has been associated with the pathogenesis of multiple diseases, including cancer. In this study, we designed and synthesized a series of aryl sulfonamide derivatives (ASDs) to inhibit the NLRP3 inflammasome. Among these, compounds 6c , 7n , and 10 specifically inhibited NLRP3 activation at nanomolar concentrations without affecting the activation of the NLRC4 and AIM2 inflammasomes. Furthermore, we demonstrated that these compounds reduce interleukin-1β (IL-1β) production in vivo and attenuate melanoma tumor growth. Moreover, metabolic stability in liver microsomes of 6c , 7n , and 10 was studied along with plasma exposure in mice of the most interesting compound 6c . Therefore, we generated potent NLRP3 inflammasome inhibitors, which can be considered in future medicinal chemistry and pharmacological studies aimed at developing a new therapeutic approach for NLRP3 inflammasome-driven cancer.
Databáze:	MEDLINE
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