Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling

Authors and Affiliations:

Bastien Cautain¹, Francisco Castillo¹, Loana Musso², Bibiana I. Ferreira^3,4, Nuria de Pedro¹, Lorena Rodriguez Quesada¹, Susana Machado³, Francisca Vicente¹, Sabrina Dallavalle², Wolfgang Link^3,4

¹ Fundacion MEDINA, Parque Tecnológico Ciencias de la Salud, Granada, Spain, 

² DeFENS Department of Food, Environmental and Nutritional Sciences, Università di Milano, Italy, 

³ Centre for Biomedical Research (CBMR), Gambelas Campus, Faro, Portugal, 

⁴ Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, Campus de Gambelas, Faro, Portugal
 

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.

Journal: PLOS One

Link: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167491