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

Abstract

Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate the oncogene eIF4E on serine 209. This phosphorylation has been reported to be required for its oncogenic activity. To investigate if pharmacological inhibition of MNK1 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 IC(50) values less than 10 μM (2.10% hit rate). The most potent compound had an IC(50) 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.

An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis

“…Closer investigation of the Mnk2D228G-staurosporine complex using docking methods showed that the rigid planar polycyclic ring system of staurosporine lies in a flat orientation in the ATP-binding pocket and the lactam ring forms a total of two hydrogen bonds with the Glu160 and Met162 residues in the hinge region [5]. Such an observation is consistent with the results obtained from a previous study, in which different docking methods were used to replicate the data [21]. Notably, the gatekeeper residue Phe159 in Mnk2 may assist in the formation of favorable hydrophobic interactions with the polycyclic ring system of staurosporine, possibly stabilizing the overall protein-ligand complex [3].…”

Zinc interference with Cd‐induced hormetic effect in differentiated Caco‐2 cells: Evidence for inhibition downstream ERK activation

“…As shown in Figure , Cd‐induced ERK1/2 activation did not increase the level of p‐eIF4E. On the contrary, levels of p‐eIF4E and eIF4E in cells exposed to Cd were about half that of control cells without additional effect of LJI308 or ETP‐45835 which inhibits RSK and MNK1/2, respectively . Accordingly, none of these inhibitors modified the Cd‐induced increase in MTT‐reducing activity (Figure C).…”

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…Their catalytic domains share 78% sequence identity and the active sites are highly conserved [25,57]. MNK1 and MNK2 display the canonical bilobal arrangement of the ATP-binding cleft sandwiched in between the C-terminal and N-terminal lobes.…”