title: Imidazoquinoxaline derivative EAPB0503: A promising drug targeting mutant nucleophosmin 1 in acute myeloid leukemia.
abstract: Nucleophosmin 1 (NPM1) is a nucleocytoplasmic shuttling protein mainly localized in the nucleolus. NPM1 is frequently mutated in acute myeloid leukemia (AML). NPM1c oligomerizes with wild-type nucleophosmin 1 (wt-NPM1), and this leads to its continuous cytoplasmic delocalization and contributes to leukemogenesis. Recent studies have shown that Cytoplasmic NPM1 (NPM1c) degradation leads to growth arrest and apoptosis of NPM1c AML cells and corrects wt-NPM1 normal nucleolar localization.
  
  
  
  AML cells expressing wt-NPM1 or NPM1c or transfected with wt-NPM1 or NPM1c as well as wt-NPM1 and NPM1c AML xenograft mice were used. Cell growth was assessed with trypan blue or a CellTiter 96 proliferation kit. The cell cycle was studied with a propidium iodide (PI) assay. Caspase-mediated intrinsic apoptosis was assessed with annexin V/PI, the mitochondrial membrane potential, and poly(adenosine diphosphate ribose) polymerase cleavage. The expression of NPM1, p53, phosphorylated p53, and p21 was analyzed via immunoblotting. Localization was performed with confocal microscopy. The leukemia burden was evaluated by flow cytometry with an anti-human CD45 antibody.
  
  
  
  The imidazoquinoxaline 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503) induced selective proteasome-mediated degradation of NPM1c, restored wt-NPM1 nucleolar localization in NPM1c AML cells, and thus yielded selective growth arrest and apoptosis. Introducing NPM1c to cells normally harboring wt-NPM1 sensitized them to EAPB0503 and led to their growth arrest. Moreover, EAPB0503 selectively reduced the leukemia burden in NPM1c AML xenograft mice.
  
  
  
  These findings further reinforce the idea of targeting the NPM1c oncoprotein to eradicate leukemic cells and warrant a broader preclinical evaluation and then a clinical evaluation of this promising drug. Cancer 2017;123:1662-1673. © 2017 American Cancer Society.
authors.affiliation: Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.|Max Mousseron Institute of Biomolecules, Faculty of Pharmacy, Montpellier University, Montpellier, France.
authors.forename: Ali I
authors.initials: AI
authors.lastname: Nabbouh
authors.affiliation: Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.|Department of Cell Biology, Anatomy, and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
authors.forename: Rita S
authors.initials: RS
authors.lastname: Hleihel
authors.affiliation: Department of Biology, Faculty of Science, Lebanese University, Beirut, Lebanon.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Saliba
authors.affiliation: Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.|Department of Experimental Pathology, Microbiology, and Immunology, American University of Beirut, Beirut, Lebanon.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Karam
authors.affiliation: Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.|Department of Experimental Pathology, Microbiology, and Immunology, American University of Beirut, Beirut, Lebanon.
authors.forename: Maguy H
authors.initials: MH
authors.lastname: Hamie
authors.affiliation: National Institute of Health and Medical Research Unit 944, Collège de France, Paris, France.
authors.forename: Hsin-Chieh J M
authors.initials: HJM
authors.lastname: Wu
authors.affiliation: National Institute of Health and Medical Research Unit 944, Collège de France, Paris, France.
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Berthier
authors.affiliation: Department of Experimental Medicine, McGill University, Montreal, Canada.
authors.forename: Nadim M
authors.initials: NM
authors.lastname: Tawil
authors.affiliation: Max Mousseron Institute of Biomolecules, Faculty of Pharmacy, Montpellier University, Montpellier, France.
authors.forename: Pierre-Antoine A
authors.initials: PA
authors.lastname: Bonnet
authors.affiliation: Max Mousseron Institute of Biomolecules, Faculty of Pharmacy, Montpellier University, Montpellier, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Deleuze-Masquefa
authors.affiliation: Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.|Department of Experimental Pathology, Microbiology, and Immunology, American University of Beirut, Beirut, Lebanon.
authors.forename: Hiba A
authors.initials: HA
authors.lastname: El Hajj
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D018613:Microscopy, Confocal; D050505:Mutant Proteins / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C555838:EAPB0503; D050505:Mutant Proteins; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D011810:Quinoxalines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; D011065:Poly(ADP-ribose) Polymerases
keywords: 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503); acute myeloid leukemia; apoptosis; nucleophosmin 1; xenograft mice