Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold

Xin Jin, James Merrett, Sheng Tong, Bartholomew Flower, Jianling Xie, Rilei Yu, Shuye Tian, Ling Gao, Jiajun Zhao, Xuemin Wang, Tao Jiang, Christopher Proud

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9 Citations (Scopus)

Abstract

The mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate eukaryotic initiation factor 4E (eIF4E) and play important roles in promoting tumorigenesis and metabolic disease. Thus, inhibiting these enzymes might be valuable in the treatment of such conditions. We designed and synthesized a series of 4-((4-fluoro-2-isopropoxyphenyl)amino)-5-methylthieno[2,3-d]pyrimidine derivatives, and evaluated their inhibitory activity against the MNKs. We found 15 compounds that were active as MNK inhibitors and that one in particular, designated MNK-7g, which was potent against MNK1 and substantially more potent against MNK2. The compound MNK-7g did not affect other signaling pathways tested and had no adverse effects on cell viability. As expected from earlier studies, MNK-7g also inhibited cell migration. Therefore, the compound MNK-7g, which forms an ionic bond with Asp226 in MNK2 and possesses a substituted aniline in a thieno[2,3-d] pyrimidine structure, is a promising starting point for the future development of novel drugs for treating or managing cancer and metabolic disease.

Original languageEnglish
Pages (from-to)735-751
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume162
DOIs
Publication statusPublished - 15 Jan 2019

Keywords

  • Mnk
  • Selective inhibitor
  • Thieno[2,3-d]pyrimidine
  • eIF4E inhibition

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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