2. Academic Validation
  3. Design, synthesis, and evaluation of furo[3,2-c]pyridine-based MNK1/2 inhibitors for the treatment of colorectal cancer

Design, synthesis, and evaluation of furo[3,2-c]pyridine-based MNK1/2 inhibitors for the treatment of colorectal cancer

  • Eur J Med Chem. 2026 Jul 5:311:118853. doi: 10.1016/j.ejmech.2026.118853.
Xinrui Yuan 1,  Zeru Wang 1,  Xihan Cui 1,  Wenjing Xia 1,  Yiming Liu 1,  Zijie Sun 1,  Yifeng Pei 2,  Dezhong Guan 2,  Hongyan Xu 1,  Lei Hu 3,  Chao-Yie Yang 4,  Huibin Zhang 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212000, PR China.
  • 2 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 3 School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212000, PR China. Electronic address: [email protected].
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38103, United States. Electronic address: [email protected].
  • 5 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 41967369 DOI: 10.1016/j.ejmech.2026.118853
Abstract

Mitogen-activated protein kinase-interacting kinase 1 and 2 (MNK1/2) regulate the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), which is critical for mRNA translation initiation. Herein, we reported the discovery and development of a series of furo[3,2-c]pyridine-containing compounds, exhibiting nanomolar potency against both MNK1 and MNK2. A representative compound 34 displayed potent MNK1 and MNK2 inhibitory activity (MNK1/2 IC50 = 1.2/1.3 nM) with high selectivity. This compound reduced the phosphorylation of eIF4E and decreased the expression of Mcl-1 and Cyclin D1 in CT26 colorectal tumor cells. Oral administration of 34 alone inhibited tumor growth in CT26 mouse model. Moreover, the combination of 34 with anti-mPD-1 antibody achieved a superior antitumor effect with increased CD8+ T cell infiltration. Overall, this work identifies a promising lead compound for the development of MNK inhibitors as small-molecule therapeutics against colorectal Cancer.

Keywords

Colorectal cancer; MNK; MNK inhibitor; eIF4E.

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