title: 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 G1 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.
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research, Centre for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Theodosia
authors.initials: T
authors.lastname: Teo
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research, Centre for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Frankie
authors.initials: F
authors.lastname: Lam
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research, Centre for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Yu
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research, Centre for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research, Centre for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Sunita K C
authors.initials: SK
authors.lastname: Basnet
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research, Centre for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Hugo
authors.initials: H
authors.lastname: Albrecht
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research, Centre for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sykes
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research, Centre for Cancer Biology, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia shudong.wang@unisa.edu.au.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: C000601056:4-((4-fluoro-2-isopropoxyphenyl)amino)-5-methylthieno(2,3-d)pyrimidine-6-carboxylic acid; C000601057:4-((4-fluoro-2-isopropoxyphenyl)amino)-N-(2-methoxyethyl)-5-methylthieno(2,3-d)pyrimidine-6-carboxamide; D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; C491395:MKNK1 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases