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Eur J Med Chem. 2019 Jan 15;162:735-751. doi: 10.1016/j.ejmech.2018.10.070. Epub 2018 Nov 2.

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

Author information

1
School of Medicine and Pharmacy, Ocean University of China, and Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
2
Nutrition & Metabolism, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia.
3
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.
4
Nutrition & Metabolism, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia.
5
School of Medicine and Pharmacy, Ocean University of China, and Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China. Electronic address: jiangtao@ouc.edu.cn.
6
Nutrition & Metabolism, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia. Electronic address: Christopher.Proud@sahmri.com.

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.

KEYWORDS:

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

PMID:
30496989
DOI:
10.1016/j.ejmech.2018.10.070
[Indexed for MEDLINE]

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