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

Ahmed M Abdelaziz; Sunita K C Basnet; Saiful Islam; Manjun Li; Solomon Tadesse; Hugo Albrecht; Cobus Gerber; Mingfeng Yu; Shudong Wang

doi:10.1016/j.bmcl.2019.07.043

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. Epub 2019 Jul 23.

Authors

Ahmed M Abdelaziz¹, Sunita K C Basnet¹, Saiful Islam¹, Manjun Li¹, Solomon Tadesse¹, Hugo Albrecht¹, Cobus Gerber¹, Mingfeng Yu², Shudong Wang³

Affiliations

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: mingfeng.yu@unisa.edu.au.
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: shudong.wang@unisa.edu.au.

PMID: 31362920
DOI: 10.1016/j.bmcl.2019.07.043

Abstract

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.

Keywords: Anti-cancer; Inhibitor; Mnk; eFT508; eIF4E.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclohexanes / chemistry
Cyclohexanes / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Pyridines / chemistry
Pyridines / pharmacology*
Spiro Compounds / chemistry
Spiro Compounds / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Cyclohexanes
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Pyridines
Spiro Compounds
Cyclohexane
MKNK1 protein, human
MKNK2 protein, human
Protein Serine-Threonine Kinases
pyridine