Small molecules bind human mTOR protein and inhibit mTORC1 specifically.

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Mechanistic target of rapamycin (mTOR) inhibition is a validated anti-cancer strategy.
• mTOR functions in two complexes, mTORC1 and mTORC2, with mTORC1 often dysregulated in tumors.
• Identifying novel mTORC1-specific inhibitors is crucial for targeted cancer therapy.

Purpose of the Study:

• To screen small molecule drugs for novel modulators of mTOR pathways.
• To identify compounds that specifically inhibit mTORC1 activity.
• To explore the therapeutic potential of mTORC1-specific inhibitors in cancer.

Main Methods:

• Screened 1600 small molecule human drugs using biolayer interferometry for mTOR protein binding.
• Assessed functional specificity of binders via S6Kinase and Akt phosphorylation assays.
• Investigated dose-dependent inhibition and chemical analog activity.

Main Results:

• Identified several dose-dependent mTOR binders across diverse chemical scaffolds.
• Discovered three compounds (carvedilol, testosterone propionate, hydroxyprogesterone) inhibiting both mTORC1 and mTORC2.
• Cinnarizine was identified as a novel mTORC1-specific inhibitor, with some analogs showing similar activity.

Conclusions:

• Cinnarizine and related piperazines represent a novel class of mTORC1-specific inhibitors.
• The piperazine scaffold holds potential for developing targeted therapies for mTORC1-activated tumors.
• Piperazine-based mTOR inhibitors could offer a new chemotherapeutic strategy with demonstrated in vitro anti-cancer activity.