期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 29, 期 18, 页码 2650-2654出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.07.043
关键词
Mnk; eIF4E; Inhibitor; Anti-cancer; eFT508
资金
- Australian Government National Health and Medical Research Council [1050825]
- South Australian Health and Medical Research Institute, Beat Cancer Project Principal Cancer Research Fellowship
- Australian Government Research Training Program Scholarship
Post-translational modulation of eIF4E through phosphorylation by Mnks is highly integral to the pathogenesis of different cancers. Therefore, inhibition of Mnks offers a strategy for cancer treatment. Herein, a series of 2' H-spiro[cyclohexane-1,3'-imidazo[1,5-a] pyridine]-1', 5'-dione derivatives is presented as Mnk inhibitors. Some of them showed sub-micromolar to low nanomolar inhibitory activities against Mnk1/2 with a high level of selectivity for both kinases over CDKs. Biochemical assays revealed that compounds 4c and 4t are non-ATP-competitive inhibitors of Mnks. Lead compound 4t demonstrated a high selectivity for Mnk1/2 over a selection of 51 kinases, and displayed anti-proliferative activities against a panel of cancer cell lines. However, this compound in combination with our in-house CDK4/6 inhibitor 83 did not show a synergistic effect in A2780 ovarian cancer cells, suggesting that caution be exercised in the selection of an agent to be combined with an Mnk inhibitor.
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