Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Targeting the kinases MNK1 and MNK2 hasemerged as a valuable strategy in oncology. However, most ofthe advanced inhibitors are acting in an adenosine triphosphate(ATP)-competitive mode, precluding the evaluation of differentbinding modes in preclinical settings. Using rational design, weidentified and validated the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathwayanalysis confirmed a direct effect of the hit compoundEB1onMNKs, and in line with the reported function of these kinases,EB1only affects the growth of tumor but not normal cells. Molecularmodeling revealed the binding ofEB1to the inactive conformationof MNK1 and the interaction with the specific DFD motif. Thisnovel 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 byEB1represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.