Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy.
Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy.
J Med Chem. 2023 Apr 13;66(7):5223-5241. doi: 10.1021/acs.jmedchem.3c00175. Epub 2023 Mar 27.
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 , , and 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 and attenuate melanoma tumor growth. Moreover, metabolic stability in liver microsomes of , , and was studied along with plasma exposure in mice of the most interesting compound . 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.
NLRP3 炎性体是先天免疫的关键组成部分，可感知多种病原体和宿主来源的分子。然而，其异常激活与多种疾病的发病机制有关，包括癌症。在这项研究中，我们设计并合成了一系列芳基磺酰胺衍生物 (ASD) 以抑制 NLRP3 炎性体。在这些化合物中，化合物 、 和 特异性地以纳摩尔浓度抑制 NLRP3 的激活，而不影响 NLRC4 和 AIM2 炎性体的激活。此外，我们证明这些化合物可减少白细胞介素-1β（IL-1β）的产生 并减弱黑色素瘤肿瘤的生长。此外，还研究了 在肝微粒体中的代谢稳定性 ，并在最有趣的化合物 的小鼠血浆中检测了其暴露情况。因此，我们生成了有效的 NLRP3 炎性体抑制剂，这可在未来的医学化学和药理学研究中得到考虑，旨在开发针对 NLRP3 炎性体驱动的癌症的新治疗方法。
