程序性细胞死亡
PI3K/AKT/mTOR通路
细胞凋亡
细胞生物学
简编
化学
生物
生物化学
历史
考古
作者
Megan Conlon,Carson Poltorack,Giovanni C. Forcina,David A. Armenta,Melodie Mallais,Marcos A. Perez,Alex Wells,Alexis Kahanu,Leslie Magtanong,Jennifer L. Watts,Derek A. Pratt,Scott J. Dixon
标识
DOI:10.1038/s41589-021-00751-4
摘要
Cell death can be executed by regulated apoptotic and nonapoptotic 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.
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