Design, Synthesis, and Biological Evaluation of a Novel NIK Inhibitor with Anti-Inflammatory and Hepatoprotective Effects for Sepsis Treatment
Nanxia Zhang, Shige Shen, Mengyu Yang, Sijie He, Chunxiao Liu, Hongmei Li, Tao Lu, Haichun Liu, Qinghua Hu, Weifang Tang, Yadong Chen
Abstract
NIK plays a crucial role in the noncanonical NF-κB signaling pathway associated with diverse inflammatory and autoimmune diseases. Our study presents compound 54, a novel NIK inhibitor, designed through a structure-based scaffold-hopping approach from the previously identified B022. Compound 54 demonstrates remarkable selectivity and potency against NIK both in vitro and in vivo, effectively suppressing pro-inflammatory cytokines and nitric oxide production. In mouse models, compound 54 protected against LPS-induced systemic sepsis, reducing AST, ALT, and AKP liver injury markers. Additionally, it also attenuates sepsis-induced lung and kidney damage. Mechanistically, compound 54 blocks the noncanonical NF-κB signaling pathway by targeting NIK, preventing p100 to p52 processing. This work reveals a novel class of NIK inhibitors with significant potential for sepsis therapy.