MAP Kinase-Interacting Kinases—Emerging Targets against Cancer

Abstract

Mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) regulate the initiation of translation through phosphorylation of eukaryotic initiation factor 4E (eIF4E). Mnk-mediated eIF4E activation promotes cancer development and progression. While the phosphorylation of eIF4E is necessary for oncogenic transformation, the kinase activity of Mnks seems dispensable for normal development. For this reason, pharmacological inhibition of Mnks could represent an ideal mechanism-based and nontoxic therapeutic strategy for cancer treatment. In this review, we discuss the current understanding of Mnk biological roles, structures, and functions, as well as clinical implications. Importantly, we propose different strategies for identification of highly selective small molecule inhibitors of Mnks, including exploring a structural feature of their kinase domain, DFD motif, which is unique within the human kinome. We also argue that a combined targeting of Mnks and other pathways should be considered given the complexity of cancer.

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…MNK1a has low basal activity, and is activated and tightly regulated by ERK and p38 kinases in response to mitogens and stress [25,48]. MNK2 displays high basal activity and is predominantly regulated by ERK1/2, although MNK2a is regulated by mTORC1 through at least one site in its C-terminal region [49,50].…”

Pharmacologic Inhibition of MNKs in Acute Myeloid Leukemia

“…The oncogenic role of eIF4E has been reported in the cell cycle progression (Diab et al, 2014a). D-type cyclins, as G 1 progression factors, play a vital role in enhancing the G 1 to S transition through binding to CDK4/6 (Sherr, 1995).…”

“…D-type cyclins, as G 1 progression factors, play a vital role in enhancing the G 1 to S transition through binding to CDK4/6 (Sherr, 1995). Elevated eIF4E levels have been shown to enhance the translational levels of a wide array of malignancy-related mRNAs involved in the regulation of cell senescence, proliferation, and apoptosis, including cyclin D1 and Mcl-1 (Zimmer et al, 2000), whereas the oncogenic functions of eIF4E are closely linked to its phosphorylation by Mnks Diab et al, 2014a). Consistent with previous studies (Zhang et al, 2008;Diab et al, 2014b;Teo et al, 2015), Mnk inhibitors in the current study triggered a cell cycle arrest in both MOLM-13 and MV4-11 cells by disrupting the transition of the G 1 phase to the S phase.…”

Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo

“…eIF4E is a key component of the cap-binding complex required for mRNA translation of mitogenic proteins, including cyclins, c-Myc, and Bcl-xl, and its activity has been linked to leukemogenesis and malignant cell proliferation. [7][8][9] The phosphorylation and activation of eIF4E by Mnk1/2 on serine 209 (Ser209) is critical for its oncogenic activity. 10,11 As Mnk1/2 double knockout mice have a normal phenotype, 12 Mnk1/2 are attractive targets for cancer therapy as their inhibition could conceivably target selectively malignant cells.…”