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

Research output: Contribution to journalArticle

2 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.

LanguageEnglish
Pages735-751
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
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

Cite this

Jin, Xin ; Merrett, James ; Tong, Sheng ; Flower, Bartholomew ; Xie, Jianling ; Yu, Rilei ; Tian, Shuye ; Gao, Ling ; Zhao, Jiajun ; Wang, Xuemin ; Jiang, Tao ; Proud, Christopher. / Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold. In: European Journal of Medicinal Chemistry. 2019 ; pp. 735-751.
@article{d3294ed2a49f4e81b5f7f84c4f5ac7e5,
title = "Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold",
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",
author = "Xin Jin and James Merrett and Sheng Tong and Bartholomew Flower and Jianling Xie and Rilei Yu and Shuye Tian and Ling Gao and Jiajun Zhao and Xuemin Wang and Tao Jiang and Christopher Proud",
year = "2019",
month = "1",
day = "15",
doi = "10.1016/j.ejmech.2018.10.070",
language = "English",
pages = "735--751",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold. / Jin, Xin; Merrett, James; Tong, Sheng; Flower, Bartholomew; Xie, Jianling; Yu, Rilei; Tian, Shuye; Gao, Ling; Zhao, Jiajun; Wang, Xuemin; Jiang, Tao; Proud, Christopher.

In: European Journal of Medicinal Chemistry, 15.01.2019, p. 735-751.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Design, synthesis and activity of Mnk1 and Mnk2 selective inhibitors containing thieno[2,3-d]pyrimidine scaffold

AU - Jin, Xin

AU - Merrett, James

AU - Tong, Sheng

AU - Flower, Bartholomew

AU - Xie, Jianling

AU - Yu, Rilei

AU - Tian, Shuye

AU - Gao, Ling

AU - Zhao, Jiajun

AU - Wang, Xuemin

AU - Jiang, Tao

AU - Proud, Christopher

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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.

AB - 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.

KW - Mnk

KW - Selective inhibitor

KW - Thieno[2,3-d]pyrimidine

KW - eIF4E inhibition

UR - http://www.scopus.com/inward/record.url?scp=85057136408&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2018.10.070

DO - 10.1016/j.ejmech.2018.10.070

M3 - Article

SP - 735

EP - 751

JO - European Journal of Medicinal Chemistry

T2 - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -