Discovery of Mitogen-Activated Protein Kinase-Interacting Kinase 1 Inhibitors by a Comprehensive Fragment-Oriented Virtual Screening Approach

Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK 1 and MNK 2) phosphorylate the oncogene eI F4E on serine 209. This phosphorylation has been reported to be required for its oncogenic activity. To investigate if pharmacological inhibition of MNK 1 could be useful for the treatment of cancers, we pursued a comprehensive virtual screening approach to rapidly identify pharmacological tools for target validation and to find optimal starting points for a plausible medicinal chemistry project. A collection of 1236 compounds, selected from a library of 42 168 compounds and a database of 18.8 million structures, were assayed. Of the identified hits, 26 were found to have IC50 values less than 10 mu M (2. 10% hit rate). The most potent compound had an IC50 value of 117 nM, and 73.1% of these hits were fragments. The hits were characterized by a high ligand efficiency (0.32-0.52 kcal/mol per heavy atom). Ten different chemical scaffolds were represented, giving a chemotype/hit ratio of 0.38.