title: Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling.
abstract: FOXO factors are tumour suppressor proteins commonly inactivated in human tumours by posttranslational modifications. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. Therefore, the pharmacological activation of FOXO proteins is considered as an attractive therapeutic approach to treat cancer and age-related diseases. In order to identify agents capable of activating FOXOs, we tested a collection of small chemical compounds using image-based high content screening technology. Here, we report the discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator. Compound 1a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a and FOXO1 in U2OS cells in a dose-dependent manner. This activity does not affect the subcellular localization of other cellular proteins including NFkB or inhibit CRM1-mediated nuclear export. Furthermore, compound 1a shows a potent antiproliferative effect in human cancer cell lines.
authors.affiliation: Fundacion MEDINA, Parque Tecnológico Ciencias de la Salud, Granada, Spain.
authors.forename: Bastien
authors.initials: B
authors.lastname: Cautain
authors.affiliation: Fundacion MEDINA, Parque Tecnológico Ciencias de la Salud, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Castillo
authors.affiliation: DeFENS Department of Food, Environmental and Nutritional Sciences, Università di Milano, Italy.
authors.forename: Loana
authors.initials: L
authors.lastname: Musso
authors.affiliation: Centre for Biomedical Research (CBMR), Gambelas Campus, Faro, Portugal.|Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Campus de Gambelas, Faro, Portugal.
authors.forename: Bibiana I
authors.initials: BI
authors.lastname: Ferreira
authors.affiliation: Fundacion MEDINA, Parque Tecnológico Ciencias de la Salud, Granada, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: de Pedro
authors.affiliation: Fundacion MEDINA, Parque Tecnológico Ciencias de la Salud, Granada, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Rodriguez Quesada
authors.affiliation: Centre for Biomedical Research (CBMR), Gambelas Campus, Faro, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Machado
authors.affiliation: Fundacion MEDINA, Parque Tecnológico Ciencias de la Salud, Granada, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.affiliation: DeFENS Department of Food, Environmental and Nutritional Sciences, Università di Milano, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.affiliation: Centre for Biomedical Research (CBMR), Gambelas Campus, Faro, Portugal.|Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Campus de Gambelas, Faro, Portugal.
authors.forename: Wolfgang
authors.identifier: http://orcid.org/0000-0002-3340-5165
authors.initials: W
authors.lastname: Link
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D008956:Models, Chemical; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; C000621379:LOM612; D009285:Naphthoquinones; D054852:Small Molecule Libraries; D013844:Thiazoles