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

doi:10.1021/acsmedchemlett.2c00442

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

ACS Med Chem Lett. 2022 Dec 15;14(1):83-91. doi: 10.1021/acsmedchemlett.2c00442. eCollection 2023 Jan 12.

Authors

Xin Jin^{1

2

3}, Tingting Qiu¹, Jianling Xie², Xianfeng Wei¹, Xuemin Wang^{2

4}, Rilei Yu¹, Christopher Proud^{2

4}, Tao Jiang¹

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 266237, China.
² Lifelong Health Theme, South Australian Health & Medical Research Institute, North Terrace, Adelaide, South Australia 5000, Australia.
³ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
⁴ School of Biomedical Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.

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.