Excessive phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) plays a major role in the dysregulation of mRNA translation and the activation of tumor cell signaling. eIF4E is exclusively phosphorylated by mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) on Ser209. So， MNK1/2 inhibitors could decrease the level of p-eIF4E and regulate tumor-associated signaling pathways. A series of pyridone-aminal derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against hematologic cancer cell lines. In particular， compound... More
Excessive phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) plays a major role in the dysregulation of mRNA translation and the activation of tumor cell signaling. eIF4E is exclusively phosphorylated by mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) on Ser209. So， MNK1/2 inhibitors could decrease the level of p-eIF4E and regulate tumor-associated signaling pathways. A series of pyridone-aminal derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against hematologic cancer cell lines. In particular， compound 42i (MNK1 IC?=?7.0?nM; MNK2 IC?=?6.1?nM) proved to be the most potent compound against TMD-8 cell line with IC value of 0.91?μM. Furthermore， 42i could block the phosphorylation level of eIF4E in CT-26 cell line， and 42i inhibited the tumor growth of CT-26 allograft model significantly. These results indicated that compound 42i was a promising MNK1/2 inhibitor for the potent treatment of colon cancer.
