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-<i>b</i>]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound <b>EB1</b> on MNKs, and in line with the reported function of these kinases, <b>EB1</b> only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of <b>EB1</b> 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 <b>EB1</b> represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.