Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Targeting the kinases
MNK1 and MNK2 has emerged as a valuable strategy
in oncology. However, most of the advanced inhibitors are acting in
an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation
of different binding modes in preclinical settings. Using rational
design, we identified and validated the 4,6-diaryl-pyrazolo­[3,4-b]­pyridin-3-amine scaffold as the core for MNK inhibitors.
Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these
kinases, EB1 only affects the growth of tumor but not
normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the
specific DFD motif. This novel mode of action appears to be superior
to the ATP-competitive inhibitors, which render the protein in a pseudo-active
state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development
of a novel generation of MNK inhibitors.