The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3. In this study, we present the identification of a novel chemical class exhibiting selective and potent inhibition of the NLRP3 inflammasome. Through a comprehensive structure-activity relationship (SAR) campaign, we optimized the lead molecule, compound A, for in vivo applications. Extensive in vitro and in vivo characterization of compound A confirmed the high selectivity and potency positioning compound A as a promising clinical candidate for diseases associated with aberrant NLRP3 activity. This research contributes to the ongoing efforts in developing targeted therapies for conditions involving NLRP3-mediated inflammation, opening avenues for further preclinical and clinical investigations.

中文翻译：

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从细胞表型筛选到临床候选：选择性靶向 NLRP3 炎性小体。


NLRP3 炎性小体在宿主防御中起关键作用，并驱动炎症对抗微生物威胁、晶体和危险相关分子模式 （DAMP）。NLRP3 活性失调与各种人类疾病有关，使其成为一个有吸引力的治疗靶点。NLRP3 突变患者患有 Cryopyrin 相关周期性综合征 （CAPS），强调了调节 NLRP3 的临床意义。在这项研究中，我们提出了一种新型化学类别的鉴定，该化学类别表现出对 NLRP3 炎性小体的选择性和有效抑制作用。通过全面的构效关系 （SAR） 活动，我们优化了用于体内应用的先导分子化合物 A。化合物 A 的广泛体外和体内表征证实了化合物 A 的高选择性和效力，使其成为与 NLRP3 活性异常相关的疾病的有前途的临床候选药物。这项研究有助于为涉及 NLRP3 介导的炎症病症开发靶向疗法的持续努力，为进一步的临床前和临床研究开辟了途径。