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Rapid Synthesis and Screening of Chemically Activated Transcription Factors with GFP-based Reporters
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Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling

Bastien Cautain1, Francisco Castillo1, Loana Musso2

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

Plos One
|December 10, 2016
PubMed

Insights

Researchers discovered LOM612, a novel compound that activates FOXO proteins, which are crucial tumor suppressors. This finding offers a potential new therapeutic strategy for cancer and age-related diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • FOXO factors are tumor suppressor proteins frequently inactivated in human cancers.
  • Genetic variations in FOXO3a are linked to human longevity, highlighting FOXO's role in aging.
  • Pharmacological activation of FOXO proteins is a promising therapeutic strategy for cancer and age-related diseases.

Purpose of the Study:

  • To identify novel small chemical compounds that activate FOXO proteins.
  • To discover potent FOXO-activating agents for potential therapeutic applications.

Main Methods:

  • Utilized image-based high-content screening technology to test a chemical compound library.
  • Synthesized and evaluated LOM612 (compound 1a), an isothiazolonaphthoquinone derivative.
  • Assessed the effect of compound 1a on FOXO3a reporter and endogenous FOXO1/3a nuclear translocation in U2OS cells.

Main Results:

  • Identified LOM612 (compound 1a) as a potent FOXO relocator.
  • Compound 1a induced dose-dependent nuclear translocation of FOXO3a reporter and endogenous FOXO1/3a.
  • Compound 1a did not affect the localization of NFkB or inhibit CRM1-mediated nuclear export.
  • Compound 1a demonstrated significant antiproliferative effects in human cancer cell lines.

Conclusions:

  • LOM612 (compound 1a) is a novel isothiazolonaphthoquinone that effectively activates FOXO proteins.
  • Compound 1a's ability to induce FOXO nuclear translocation and inhibit cancer cell proliferation supports its therapeutic potential.
  • Further research into LOM612 could lead to new treatments for cancer and age-related conditions.

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