1. A compendium of kinetic modulatory profiles identifies ferroptosis regulators
- Author
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David A. Armenta, Megan Conlon, Alexis Kahanu, Alex Wells, Carson D. Poltorack, Melodie Mallais, Derek A. Pratt, Leslie Magtanong, Giovanni C. Forcina, Marcos A. Perez, Jennifer L. Watts, and Scott J. Dixon
- Subjects
Programmed cell death ,Indoles ,Apoptosis ,Iron Chelating Agents ,Antioxidants ,Article ,law.invention ,Small Molecule Libraries ,03 medical and health sciences ,In vivo ,law ,Animals ,Ferroptosis ,Humans ,Amino Acids ,Molecular Biology ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,0303 health sciences ,Cell Death ,Cell-Free System ,biology ,Chemistry ,TOR Serine-Threonine Kinases ,030302 biochemistry & molecular biology ,Electrophoresis, Capillary ,Cell Biology ,Small molecule ,In vitro ,Cell biology ,Kinetics ,biology.protein ,Suppressor - Abstract
Cell death can be executed by regulated apoptotic and non-apoptotic pathways, including the iron-dependent process of ferroptosis. Small molecules are essential tools for studying the regulation of cell death. Using time-lapse imaging, and a library of 1,833 bioactive compounds, we assembled a large compendium of kinetic cell death modulatory profiles for inducers of apoptosis and ferroptosis. From this dataset we identify dozens of ferroptosis suppressors, including numerous compounds that appear to act via cryptic off-target antioxidant or iron chelating activities. We show that the FDA-approved drug bazedoxifene acts as a potent radical trapping antioxidant inhibitor of ferroptosis both in vitro and in vivo. ATP-competitive mechanistic target of rapamycin (mTOR) inhibitors, by contrast, are on-target ferroptosis inhibitors. Further investigation revealed both mTOR-dependent and mTOR-independent mechanisms that link amino acid metabolism to ferroptosis sensitivity. These results highlight kinetic modulatory profiling as a useful tool to investigate cell death regulation.
- Published
- 2021
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