Using Imidazo[2,1- b][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors

Xin Jin, Tingting Qiu, Jianling Xie, Xianfeng Wei, Xuemin Wang, Rilei Yu, Christopher Proud, Tao Jiang

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Mitogen-activated protein kinase-interacting protein kinases (MNKs) phosphorylate eukaryotic initiation factor 4E (eIF4E) and regulate the processes of cell proliferation, cell cycle, and migration and invasion of cancer cells. Selectively inhibiting the activity of MNKs could be effective in treating cancers. In this study, we report a series of novel MNK inhibitors with an imidazo[2,1-b][1,3,4]thiadiazol scaffold, from which, compound 18 inhibited the phosphorylation of eIF4E in various cancer cell lines potently. Compound 18 was more potent against MNK2 than MNK1, and decreased the levels of cyclin-B1, cyclin-D3, and MMP-3 in A549 and MDA-MB-231 cells, impaired cell growth and colony formation, arrested the cell cycle in the G0/G1 phase, and inhibited cell migration and the secretion of TNF-α, MCP-1, and IL-8 from A549 cells. It represents a starting compound to design further inhibitors that selectively target MNKs and apply in other diseases.

Original languageEnglish
Pages (from-to)83-91
Number of pages9
JournalACS Medicinal Chemistry Letters
Volume14
Issue number1
DOIs
Publication statusPublished or Issued - 12 Jan 2023

Keywords

  • Cell cycle
  • MMP-3
  • MNK
  • Migration
  • eIF4E

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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