TY - JOUR
T1 - Using Imidazo[2,1- b][1,3,4]thiadiazol Skeleton to Design and Synthesize Novel MNK Inhibitors
AU - Jin, Xin
AU - Qiu, Tingting
AU - Xie, Jianling
AU - Wei, Xianfeng
AU - Wang, Xuemin
AU - Yu, Rilei
AU - Proud, Christopher
AU - Jiang, Tao
N1 - Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.
PY - 2023/1/12
Y1 - 2023/1/12
N2 - 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.
AB - 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.
KW - Cell cycle
KW - MMP-3
KW - MNK
KW - Migration
KW - eIF4E
UR - http://www.scopus.com/inward/record.url?scp=85144462049&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.2c00442
DO - 10.1021/acsmedchemlett.2c00442
M3 - Article
AN - SCOPUS:85144462049
SN - 1948-5875
VL - 14
SP - 83
EP - 91
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 1
ER -