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

  • J Med Chem. 2024 Apr 11;67(7):5617-5641. 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
Affiliations
  • 1. School of Sciences, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 2. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 3. State Key Laboratory of Natural Medicines, School of Science, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 4. Laboratory of Molecular Design and Drug Discovery, School of Sciences, China Pharmaceutical University, Nanjing 211198, P. R. China.
PMID: 38563549 DOI: 10.1021/acs.jmedchem.3c02266
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.

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