Centre for Drug Discovery and Development, Cancer Research Institute, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
Centre for Drug Discovery and Development, Cancer Research Institute, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
Bioorg Med Chem Lett. 2019 Sep 15;29(18):2650-2654. doi: 10.1016/j.bmcl.2019.07.043. Epub 2019 Jul 23.
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.
通过 Mnks 对 eIF4E 的翻译后修饰的调节在不同癌症的发病机制中起着至关重要的作用。因此，抑制 Mnks 为癌症治疗提供了一种策略。本文报道了一系列 2'H-螺[环己烷-1,3'-咪唑并[1,5-a]吡啶]-1',5'-二酮衍生物作为 Mnk 抑制剂。其中一些化合物对 Mnk1/2 具有亚微摩尔至低纳摩尔的抑制活性，对两种激酶的选择性均高于 CDK。生化测定表明，化合物 4c 和 4t 是非 ATP 竞争性的 Mnks 抑制剂。先导化合物 4t 对 Mnk1/2 的选择性高于 51 种激酶中的一种，对一系列癌细胞系表现出抗增殖活性。然而，该化合物与我们内部的 CDK4/6 抑制剂 83 联合使用在 A2780 卵巢癌细胞中并未显示出协同作用，这表明在选择与 Mnk 抑制剂联合使用的药物时应谨慎。
