Discovery of Imidazo[2,1- b][1,3,4]thiadiazole-Based MNK Inhibitors with Anti-inflammatory Efficacy via Dual Suppression of eIF4E Phosphorylation and NF-κB Signaling

  • J Med Chem. 2026 Apr 23;69(8):9713-9731. doi: 10.1021/acs.jmedchem.6c00577.
Hongwei Li  1 ,  Huiying Zhuang  1 ,  Dianxi Zhang  1  2 ,  Tingting Qiu  1 ,  Lu Liu  2 ,  Ziyi Sunyang  1 ,  Yuqiang Han  1 ,  Rilei Yu  1  3  2 ,  Guanzhao Wu  4 ,  Ruijuan Yin  1  2 ,  Tao Jiang  1  3  2
Affiliations
  • 1. Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 2. Marine Biomedical Research Institute of Qingdao, Qingdao 266100, China.
  • 3. Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
  • 4. Department of Medical Experimental Center, Qilu Hospital (Qingdao), Shandong University, Qingdao 266035, China.
PMID: 41944589 DOI: 10.1021/acs.jmedchem.6c00577
Abstract

Mitogen-activated protein kinase-interacting kinase (MNK), a pivotal kinase downstream of MAPK signaling, is currently the only enzyme reported to be capable of phosphorylating eIF4E. This study first confirmed that MNK silencing in LPS-stimulated macrophages inhibits eIF4E phosphorylation, inflammatory polarization, and cytokine release. Based on the prior discovery that the imidazo[2,1-b][1,3,4]thiadiazole skeleton can effectively inhibit the MNK kinases, this study further designed and synthesized a series of imidazo[2,1-b][1,3,4]thiadiazole derivatives modified with sulfonyl or phosphoryl groups. Among these derivatives, compound 13 potently and selectively inhibited MNK1/2 (IC50 = 10.84/12.81 nM), exerted dose-dependent anti-inflammatory effects in LPS-induced RAW 264.7 cells, and alleviated kidney and spleen damage in the mouse model of LPS-induced inflammation. Mechanistically, 13 suppressed eIF4E phosphorylation, NF-κB signaling, and macrophage polarization, thereby reducing pro-inflammatory cytokines and oxidative stress. These results suggest that MNK inhibition is a promising strategy for treating inflammatory diseases by targeting both inflammation and oxidative stress.

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