2. Academic Validation
  3. Novel Aryl Sulfonamide Derivatives as NLRP3 Inflammasome Inhibitors for the Potential Treatment of Cancer

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

  • J Med Chem. 2023 Apr 13;66(7):5223-5241. doi: 10.1021/acs.jmedchem.3c00175.
Valentina Albanese 1,  Sonia Missiroli 2 3,  Mariasole Perrone 2 3,  Martina Fabbri 4,  Caterina Boncompagni 2 3,  Salvatore Pacifico 4,  Tiziano De Ventura 4,  Antonella Ciancetta 4,  Giulio Dondio 5,  Franz Kricek 6,  Paolo Pinton 2 3,  Remo Guerrini 3 4,  Delia Preti 4,  Carlotta Giorgi 2 3
Affiliations

Affiliations

  • 1 Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy.
  • 2 Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy.
  • 3 Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), via Fossato di Mortara 70, 44121 Ferrara, Italy.
  • 4 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.
  • 5 Aphad Srl, Via della Resistenza 65, 20090 Buccinasco, Italy.
  • 6 NBS-C Bioscience & Consulting GmbH, 1230 Vienna, Austria.
PMID: 36972104 DOI: 10.1021/acs.jmedchem.3c00175
Abstract

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.

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