Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition

Dysregulated translation of mRNA
plays a major role in tumorigenesis.
Mitogen-activated protein kinase interacting kinases (MNK)­1/2 are
key regulators of mRNA translation integrating signals from oncogenic
and immune signaling pathways through phosphorylation of eIF4E and
other mRNA binding proteins. Modulation of these key effector proteins
regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2
inhibitor, was designed to assess the potential for control of oncogene
signaling at the level of mRNA translation. The crystal structure-guided
design leverages stereoelectronic interactions unique to MNK culminating
in a novel pyridone–aminal structure described for the first
time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell
B-cell lymphoma and solid tumors, suggesting that controlling dysregulated
translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid
tumors and lymphoma. Compound 23 is the first highly
selective dual MNK inhibitor targeting dysregulated translation being
assessed clinically.