Design, Synthesis, and Biological Evaluation of a Novel NIK Inhibitor with Anti-Inflammatory and Hepatoprotective Effects for Sepsis Treatment,Journal of Medicinal Chemistry

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Design, Synthesis, and Biological Evaluation of a Novel NIK Inhibitor with Anti-Inflammatory and Hepatoprotective Effects for Sepsis Treatment
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-04-02 , DOI: 10.1021/acs.jmedchem.3c02266
Nanxia Zhang ₁ , Shige Shen ₂ , Mengyu Yang ₁ , Sijie He ₁ , Chunxiao Liu ₂ , Hongmei Li ₁ , Tao Lu _{1,

3} , Haichun Liu ₄ , Qinghua Hu ₂ , Weifang Tang ₁ , Yadong Chen _{1,

3}

Affiliation

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.

中文翻译：

具有抗炎和保肝作用的新型 NIK 抑制剂用于脓毒症治疗的设计、合成和生物学评价

NIK 在与多种炎症和自身免疫性疾病相关的非经典 NF-κB 信号通路中发挥着至关重要的作用。我们的研究提出了化合物54 ，一种新型 NIK 抑制剂，通过基于结构的支架跳跃方法从先前鉴定的 B022 中设计出来。化合物54在体外和体内均表现出显着的针对 NIK 的选择性和效力，可有效抑制促炎细胞因子和一氧化氮的产生。在小鼠模型中，化合物54可以预防 LPS 诱导的系统性脓毒症，减少 AST、ALT 和 AKP 肝损伤标志物。此外，它还可以减轻败血症引起的肺和肾损伤。从机制上讲，化合物54通过靶向 NIK 来阻断非经典 NF-κB 信号通路，从而阻止 p100 到 p52 的加工。这项工作揭示了一类新型 NIK 抑制剂，具有治疗脓毒症的巨大潜力。

更新日期：2024-04-02

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