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

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.

Discovery of Triazinone Derivatives as Novel, Specific, and Direct NLRP3 Inflammasome Inhibitors for the Treatment of DSS-Induced Ulcerative Colitis

“…Yield 73.8%. 1 (19). To a mixture of ethyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (100 mg, 0.51 mmol) in EtOH, the solution of LiOH•H 2 O in water was added.…”

“…MCC950 (2) is a well-known NLRP3 inhibitor with high specificity and strong inhibitory effect, but its phase II clinical trial of rheumatoid arthritis was suspended due to the possible hepatotoxicity . Subsequently, a large number of MCC950 analogs have emerged, − and several compounds are in the early stages of clinical research, such as ZYIL-1 (3), RG-6418 (4), and IZD-174 (5) . Among them, ZYIL-1 revealed rapid clinical improvement in CAPS patients with confirmed NLRP3 mutation during a Phase II proof-of-concept trial for CAPS-related flare-up (NCT05186051) .…”

Design, Synthesis, and Biological Evaluation of Ferulic Acid Template-Based Novel Multifunctional Ligands Targeting NLRP3 Inflammasome for the Management of Alzheimer’s Disease

“…Activation of the NLRP3 inflammasome leads to the secretion of proinflammatory cytokines like interleukin-1β and interleukin-18, as well as pyroptotic cell death, a programmed cell death associated with inflammation. , Multiple triggers, including bacterial and viral infections, released damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) from damaged or infected cells can activate the NLRP3 inflammasome . The dysregulation of this inflammasome has been implicated in various inflammatory and autoimmune conditions like AD, gout, type 2 diabetes, and multiple sclerosis. , Consequently, investigating the mechanisms that control NLRP3 inflammasome activation is an active area of research, holding promise for developing novel therapies targeting these diseases. Several inhibitors of NLRP3 inflammasome and its signaling cascade have been shown to exhibit a crucial role in regulating the microglia function and its activity .…”

SARS-CoV-2 infection as a model to study the effect of cinnamaldehyde as adjuvant therapy for viral pneumonia.

“…Accordingly, different NLRP3 in ammasome inhibitors have been reported to date, including the ones that directly inhibit the NLRP3 and those that act on its related signaling pathways [10]. Indeed, recently we identi ed a series of aryl sulfonamide derivatives (ASDs) and natural compounds with high potency and selectivity in inhibiting NLRP3 activation in vitro and in vivo [11,12]. Among all the cited inhibitors, nutraceutical compounds might be of high impact for their low side effects in prolonged treatments.…”