Synthesis and evaluation of 2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione derivatives as Mnk inhibitors
- Bioorg Med Chem Lett. 2019 Sep 15;29(18):2650-2654. doi: 10.1016/j.bmcl.2019.07.043.
- 1. 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.
- 2. 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. Electronic address: [email protected].
- 3. 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. Electronic address: [email protected].
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.