An mTOR inhibitor discovery system using drug-sensitized yeast

Area of Science:

• Molecular Biology
• Drug Discovery
• Yeast Genetics

Background:

• The target of rapamycin (TOR) pathway regulates cell growth and aging.
• Rapamycin extends lifespan but has side effects, necessitating new TOR inhibitors.
• Yeast models offer a tractable system for studying TOR and identifying inhibitors.

Purpose of the Study:

• To develop a highly sensitive yeast-based platform for identifying novel TOR inhibitors.
• To improve the detection sensitivity for known TOR inhibitors.
• To screen compounds for TOR pathway inhibitory activity.

Main Methods:

• Generated a panel of Saccharomyces cerevisiae strains with mutations in TOR pathway genes and removed drug efflux genes.
• Created a drug-sensitive yeast background for enhanced inhibitor detection.
• Tested known TOR inhibitors (Torin1, GSK2126458, AZD8055) and screened other compounds for TOR1-dependent growth inhibition.

Main Results:

• The drug-sensitive yeast system demonstrated a 200-250 fold increase in sensitivity for Torin1 and GSK2126458.
• Identified TOR1-dependent growth inhibition by AZD8055, which was not observed in wild-type yeast.
• Discovered aminophylline as a novel TOR1-dependent growth inhibitor and found no TOR inhibition by several other tested compounds.

Conclusions:

• The developed drug-sensitive yeast platform is highly effective for identifying TOR pathway inhibitors.
• This system provides a rapid, cost-efficient, and sensitive tool for drug discovery.
• The platform has the potential to accelerate the identification of new geroprotective and anti-cancer agents.