Multi-targeted MNK inhibitors as anticancer agents for AML

Mutant FMS-like tyrosine kinase 3 (FLT3) is implicated as an oncogenic driver in over 30% of acute myeloid leukemia (AML) cases. While several FLT3-targeted drugs have been approved, resistance develops rapidly through varied mechanisms, including RAS mutations. The mitogen-activated protein kinase-interacting kinases (MNK1 and MNK2) are the only kinases that phosphorylate the eukaryotic translation initiation factor 4E (eIF4E). Dysregulation of the MNK-eIF4E axis has been seen in acute myeloid leukemia (AML) and MNK inhibitors have shown antiproliferative effects in AML. The kinases, MNK1 and MNK2 are activated by p38 mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinase (ERK), downstream of FLT3 and RAS in the RAS/RAF/ERK signaling cascade. The aurora kinases (AURKA and AURKB) are also overexpressed in AML. Synergistic anticancer effects have been observed in AML for AURK inhibitors in combination with FLT3 targeted drugs. Multitargeted inhibition of varied oncogenic drivers could be anticipated to demonstrate improved anticancer effects in AML, particularly resistant AML. We have identified novel compounds as multi-targeted MNK inhibitors that bind with nanomolar potencies to MNK1, MNK2, FLT3 and AURKB. The compounds show single-digit micromolar inhibition of AML cells expressing mutant FLT3 (MV-411) and are equipotent to tomivosertib, a clinically investigated MNK inhibitor that was included as a standard for comparison. The design, synthesis, and anticancer effects of multi-targeted MNK inhibitors will be described.