Progress in developing MNK inhibitors.

The MNKs (mitogen-activated protein kinase-interacting protein kinases) phosphorylate eIF4E (eukaryotic initiation factor 4 E) at serine 209; eIF4E plays an important role in the translation of cytoplasmic mRNAs, all of which possess a 5' 'cap' structure to which eIF4E binds. Elevated levels of eIF4E, p-eIF4E and/or the MNK protein kinases have been found in many types of cancer, including solid tumors and leukemia. MNKs also play a role in metabolic disease. Regulation of the activities of MNKs (MNK1 and MNK2), control the phosphorylation of eIF4E, which in turn has a close relationship with the processes of tumor development, cell migration and invasion, and energy metabolism. MNK knock-out mice display no adverse effects on normal cells or phenotypes suggesting that MNK may be a potentially safe targets for the treatment of various cancers. Several MNK inhibitors or 'degraders' have been identified. Initially, some of the inhibitors were developed from natural products or based on other protein kinase inhibitors which inhibit multiple kinases. Subsequently, more potent and selective inhibitors for MNK1/2 have been designed and synthesized. Currently, three inhibitors (BAY1143269, eFT508 and ETC-206) are in various stages of clinical trials for the treatment of solid cancers or leukemia, either alone or combined with inhibitors of other protein kinase. In this review, we summarize the diverse MNK inhibitors that have been reported in patents and other literature, including those with activities in vitro and/or in vivo.