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

PLoS One. 2016 Dec 9;11(12):e0167491. doi: 10.1371/journal.pone.0167491. eCollection 2016.


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.

MeSH terms

  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Cytoplasm / metabolism
  • Dose-Response Relationship, Drug
  • Forkhead Box Protein O1 / metabolism*
  • Forkhead Box Protein O3 / metabolism*
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Microscopy, Confocal
  • Models, Chemical
  • Molecular Structure
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology*
  • Protein Transport / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*


  • FOXO1 protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • LOM612
  • Naphthoquinones
  • Small Molecule Libraries
  • Thiazoles

Grants and funding

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) Research Center Grant UID/BIM/04773/2013 CBMR1334. B. I. Ferreira is the recipient of a FCT 2014 research grant SFRH/BPD/100434/2014R. S. Machado is the recipient of a ProRegem grant PD/BD/114258/2016.