Mitogen-activated Protein Kinase (MAPK) Interacting Kinases 1 and 2 (MNK1 and MNK2) as Targets for Cancer Therapy: Recent Progress in the Development of MNK Inhibitors

Abstract

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.

Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation

“…MNK1 contains a zinc-binding domain with four cysteine residues located in a region encompassing a helix αG domain (residues 261–290; ref. 55). Notably, this domain is unique to the MNKs and not found in other Ca 2+ /calmodulin-dependent protein kinases (CAMK; ref.…”

“…Notably, this domain is unique to the MNKs and not found in other Ca 2+ /calmodulin-dependent protein kinases (CAMK; ref. 55). It is possible that ATO binds MNK1 to cysteines on positions C264, C268, C276, and C279.…”

“…It is possible that ATO binds MNK1 to cysteines on positions C264, C268, C276, and C279. Although the role of this region is not fully understood, it may be important for substrate binding (55). Future studies will need to be conducted to uncover the role of these cysteines in MNK1 kinase activity.…”

“…Furthermore, our study suggests a rationale for ATO when combined with MNK inhibitors in MES GBM. Novel MNK inhibitors are currently under development, which may have clinical applications (55). Furthermore, preliminary success for the treatment of GBM has been achieved by targeting other components of the translational machinery (37, 56).…”

MicroRNA Expression Profiling of Pancreatic Cancer Cell Line L3.6p1 Following B7-H4 Knockdown

“…These results implyed that B7-H4-related miRNAs might significantly affect these pathways to contribute to tumorigenesis [24-26]. It was well-known that the PI3K-Akt and MAPK signaling pathways are involved in the processes of tumor cell apoptosis and tumor development [36, 37]. Studies have shown that B7-H4 promotes lung tumor growth, progression, and metastasis through the AKT pathway [38].…”