Pharmacologic Inhibition of MNKs in Acute Myeloid Leukemia

Abstract

The Ras/Raf/MAPK and PI3K/Akt/mTOR pathways are key signaling cascades involved in the regulation of cell proliferation and survival, and have been implicated in the pathogenesis of several types of cancers, including acute myeloid leukemia (AML). The oncogenic activity of eIF4E driven by the Mnk kinases is a convergent determinant of the two cascades, suggesting that targeting the Mnk/eIF4E axis may provide therapeutic opportunity for the treatment of cancer. Herein, a potent and selective Mnk2 inhibitor (MNKI-85) and a dual-specific Mnk1 and Mnk2 inhibitor (MNKI-19), both derived from a thienopyrimidinyl chemotype, were selected to explore their antileukemic properties. MNKI-19 and MNKI-85 are effective in inhibiting the growth of AML cells that possess an M5 subtype with FLT3-internal tandem duplication mutation. Further mechanistic studies show that the downstream effects with respect to the selective Mnk1/2 kinase inhibition in AML cells causes G 1 cell cycle arrest followed by induction of apoptosis. MNKI-19 and MNKI-85 demonstrate similar Mnk2 kinase activity and cellular antiproliferative activity but exhibit different time-dependent effects on cell cycle progression and apoptosis. Collectively, this study shows that pharmacologic inhibition of both Mnk1 and Mnk2 can result in a more pronounced cellular response than targeting Mnk2 alone. However, MNKI-85, a first-in-class inhibitor of Mnk2, can be used as a powerful pharmacologic tool in studying the Mnk2/eIF4E-mediated tumorigenic mechanism. In conclusion, this study provides a better understanding of the mechanism underlying the inhibition of AML cell growth by Mnk inhibitors and suggests their potential utility as a therapeutic agent for AML.

Screening Novel Molecular Targets of Metformin in Breast Cancer by Proteomic Approach

“…Some in the second group such as SYNC, LIMD1, HMGCR, PSAP, ITGB4, FREM2, LAMB2, ITM2B, and SLC25A17 proteins (Figure 6 B). Among the interesting downregulated proteins found in treated MCF-7 is MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1), this protein may have a role in the response to cytokines and environmental stress, which may provide an effective strategy for cancer therapy ( 63 , 64 ). Another downregulated protein is the growth regulation by estrogen in breast cancer 1 (GREB1).…”

“…MKNK, a downregulated protein in treated MCF-7 cells, renders its effect on oncogenic transformation and cancer progression. This protein was found to be a potential therapeutic target in cancer treatment ( 45 , 46 , 63 , 64 ). GREB1 a protein which is originally upregulated in ER + breast cancers such as MCF-7 cells and results in upregulation of ER survival signaling through the growth factor ligand, resulting in increased growth and proliferation ( 45 , 46 , 65 , 66 ).…”

Inhibitory effects of Tomivosertib in acute myeloid leukemia

“…The pro-neoplastic activity of eIF4E is associated with its phosphorylation/activation by MNK1/2 on serine 209 [24][25][26] and correlates with enhanced mRNA translation, as well as nuclear export of mRNAs involved in tumorigenesis and cell cycle control [26][27][28][29][30][31]. Several studies have shown that pharmacological targeting of MNK1/2 results in inhibitory activity against AML cells in pre-clinical models [32][33][34][35][36][37]. However, the extent of these effects has been frequently demonstrated using MNK1/2 inhibitors that lack high selectivity against MNK1/2 [32][33][34][35][36][37].…”

Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2

“…Most pronounced cytotoxic effects have been observed in Fms-like tyrosine kinase 3 overexpressing leukemia cells (Altman et al, 2013;Lim et al, 2013;Diab et al, 2014b;Teo et al, 2015a). Accordingly the cytotoxic assay in MV4-11 cells was included in the screening cascade.…”