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 G Proud

doi:10.1016/j.ejmech.2018.10.070

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

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

Authors

Xin Jin¹, James Merrett², Sheng Tong¹, Bartholomew Flower², Jianling Xie², Rilei Yu¹, Shuye Tian², Ling Gao³, Jiajun Zhao³, Xuemin Wang⁴, Tao Jiang⁵, Christopher G Proud⁶

Affiliations

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: [email protected].
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: [email protected].

PMID: 30496989
DOI: 10.1016/j.ejmech.2018.10.070

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.

MeSH terms

Cell Movement / drug effects
Cell Survival
Drug Design*
Eukaryotic Initiation Factor-4E / metabolism
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Phosphorylation
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrimidines / therapeutic use
Signal Transduction / drug effects

Substances

Eukaryotic Initiation Factor-4E
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Pyrimidines
thieno(2,3-d)pyrimidine
MKNK1 protein, human
MKNK2 protein, human
Protein Serine-Threonine Kinases