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

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.