PT - JOURNAL ARTICLE AU - Theodosia Teo AU - Frankie Lam AU - Mingfeng Yu AU - Yuchao Yang AU - Sunita KC Basnet AU - Hugo Albrecht AU - Matthew J Sykes AU - Shudong Wang TI - Pharmacologic inhibition of Mnks in acute myeloid leukemia AID - 10.1124/mol.115.098012 DP - 2015 Jan 01 TA - Molecular Pharmacology PG - mol.115.098012 4099 - http://molpharm.aspetjournals.org/content/early/2015/06/04/mol.115.098012.short 4100 - http://molpharm.aspetjournals.org/content/early/2015/06/04/mol.115.098012.full AB - 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 AML. The oncogenic activity of eIF4E driven by 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 most potent and selective Mnk2 inhibitor MNKI-85, and the dual-specific Mnk1 and Mnk2 inhibitor MNKI-19, both derived from a thienopyrimidinyl chemo-type, are selected to explore their anti-leukemic properties. MNKI-19 and MNKI-85 are effective in inhibiting the growth of AML cells which possess an M5 subtype with FLT3-ITD mutation. Further mechanistic studies show that the downstream effects with respect to the selective Mnk1/2 kinase inhibition in AML cells causes G1 cell cycle arrest followed by induction of apoptosis. MNKI-19 and MNKI-85 demonstrate similar Mnk2 kinase activity and cellular anti-proliferative 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. MNKI-85, a first-in-class inhibitor of Mnk2, however, 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.