Design, synthesis, and evaluation of furo[3,2-c]pyridine-based MNK1/2 inhibitors for the treatment of colorectal cancer

Mitogen-activated protein kinase-interacting kinase 1 and 2 (MNK1/2) regulate the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), which is critical for mRNA translation initiation. Herein, we reported the discovery and development of a series of furo[3,2-c]pyridine-containing compounds, exhibiting nanomolar potency against both MNK1 and MNK2. A representative compound 34 displayed potent MNK1 and MNK2 inhibitory activity (MNK1/2 IC₅₀ = 1.2/1.3 nM) with high selectivity. This compound reduced the phosphorylation of eIF4E and decreased the expression of Mcl-1 and Cyclin D1 in CT26 colorectal tumor cells. Oral administration of 34 alone inhibited tumor growth in CT26 mouse model. Moreover, the combination of 34 with anti-mPD-1 antibody achieved a superior antitumor effect with increased CD8⁺ T cell infiltration. Overall, this work identifies a promising lead compound for the development of MNK inhibitors as small-molecule therapeutics against colorectal Cancer.