MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream
of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development
and progression of solid tumors and hematological malignancies has been widely
discussed, particularly in the context of cap dependent translation, regulated by phosphorylation
of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic,
cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL,
SMAD2, β-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation.
MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor
effects observed in genetic knockout and RNA interference experiments and at the
same time lack of adverse effects in dual knockout animals.
There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not
only tools for further basic research studies but also potential drugs in diseases characterized
by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive
due to the absence of potent and selective probes. Moreover, in many instances, hypotheses
have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or
cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have
been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently
running at the preclinical stage. This review aims to provide an overview of recent
progress in the development of MNK inhibitors.