title: Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases.
abstract: Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. A cell-based imaging assay that monitored the translocation of the Akt effector protein, Forkhead box O (FOXO), from the cytoplasm to the nucleus was employed to screen a collection of 33,992 small molecules. The positive compounds were used to screen kinases known to be involved in FOXO translocation. Pyrazolopyrimidine derivatives were found to be potent FOXO relocators as well as biochemical inhibitors of PI3Kalpha. A combination of virtual screening and molecular modeling led to the development of a structure-activity relationship, which indicated the preferred substituents on the pyrazolopyrimidine scaffold. This leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice.
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Link
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Serelde
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Albarran
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Obdulia
authors.initials: O
authors.lastname: Rabal
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cebriá
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Alfonso
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Fominaya
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Oliver
authors.initials: O
authors.lastname: Renner
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Peregrina
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Soilán
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Plácido A
authors.initials: PA
authors.lastname: Ceballos
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Ana-Isabel
authors.initials: AI
authors.lastname: Hernández
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Milagros
authors.initials: M
authors.lastname: Lorenzo
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pevarello
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Granda
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Guido
authors.initials: G
authors.lastname: Kurz
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Electronic address: jrbischoff@cnio.es.
authors.forename: James R
authors.initials: JR
authors.lastname: Bischoff
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002867:Chromones / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005663:Furans / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D009025:Morpholines / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005663:Furans; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; C544684:ETP 45658; C499517:FOXO3 protein, human; C522973:PI103; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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