2. Academic Validation
  3. Design, synthesis and biological evaluation of pyridone-aminal derivatives as MNK1/2 inhibitors

Design, synthesis and biological evaluation of pyridone-aminal derivatives as MNK1/2 inhibitors

  • Bioorg Med Chem. 2019 Apr 1;27(7):1211-1225. doi: 10.1016/j.bmc.2019.02.007.
Xinrui Yuan 1,  Hanshu Wu 2,  Hong Bu 1,  Peiyuan Zheng 1,  Jinpei Zhou 3,  Huibin Zhang 4
Affiliations

Affiliations

  • 1 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: jpzhou668@163.com.
  • 4 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: zhanghb80@cpu.edu.cn.
PMID: 30824167 DOI: 10.1016/j.bmc.2019.02.007
Abstract

Excessive phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) plays a major role in the dysregulation of mRNA translation and the activation of tumor cell signaling. eIF4E is exclusively phosphorylated by mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) on Ser209. So, MNK1/2 inhibitors could decrease the level of p-eIF4E and regulate tumor-associated signaling pathways. A series of pyridone-aminal derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against hematologic Cancer cell lines. In particular, compound 42i (MNK1 IC50 = 7.0 nM; MNK2 IC50 = 6.1 nM) proved to be the most potent compound against TMD-8 cell line with IC50 value of 0.91 μM. Furthermore, 42i could block the phosphorylation level of eIF4E in CT-26 cell line, and 42i inhibited the tumor growth of CT-26 allograft model significantly. These results indicated that compound 42i was a promising MNK1/2 inhibitor for the potent treatment of colon Cancer.

Keywords

MNK1/2; Pyridone–aminal; eFT508; eIF4E.

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