RT Journal Article T1 Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling A1 Cautain, Bastien A1 Castillo, Francisco A1 Musso, Loana A1 Ferreira, Bibiana I. A1 de Pedro, Nuria A1 Quesada, Lorena Rodriguez A1 Machado, Susana A1 Vicente, Francisca A1 Dallavalle, Sabrina A1 Link, Wolfgang K1 Forkhead transcription factor K1 Dual-specificity phosphatase K1 Cycloaddition reactions K1 Nitrile sulfides K1 Inhibitors K1 Cancer K1 Translocation K1 Screen K1 Potent K1 Cells AB 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. PB Public library science SN 1932-6203 YR 2016 FD 2016-12-09 LK http://hdl.handle.net/10668/19166 UL http://hdl.handle.net/10668/19166 LA en DS RISalud RD Feb 16, 2025