Synthesis and evaluation of 2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a] pyridine]-1',5'-dione derivatives as Mnk inhibitors

被引：10
|
作者：
Abdelaziz, Ahmed M. [1 ,2 ]
Basnet, Sunita K. C. [1 ,2 ]
Islam, Saiful [1 ,2 ]
Li, Manjun [1 ,2 ]
Tadesse, Solomon [1 ,2 ]
Albrecht, Hugo [1 ,2 ]
Gerber, Cobus [1 ,2 ]
Yu, Mingfeng [1 ,2 ]
Wang, Shudong [1 ,2 ]
机构：
[1] Univ South Australia, Ctr Drug Discovery & Dev, Canc Res Inst, Adelaide, SA 5001, Australia
[2] Univ South Australia, Sch Pharm & Med Sci, Adelaide, SA 5001, Australia
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 18期
基金：
英国医学研究理事会;
关键词：
Mnk; eIF4E; Inhibitor; Anti-cancer; eFT508; KINASE-INTERACTING KINASES; HIGHLY POTENT; LEUKEMIA; DISCOVERY; COMBINATION; CDK4/6;
D O I：
10.1016/j.bmcl.2019.07.043
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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.
引用
收藏
页码：2650 / 2654
页数：5
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