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A compendium of kinetic modulatory profiles identifies ferroptosis regulators

Nature chemical biology, 2021-06, Vol.17 (6), p.665-674 [Peer Reviewed Journal]

The Author(s), under exclusive licence to Springer Nature America, Inc. 2021. ;ISSN: 1552-4450 ;EISSN: 1552-4469 ;DOI: 10.1038/s41589-021-00751-4 ;PMID: 33686292

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Title:
A compendium of kinetic modulatory profiles identifies ferroptosis regulators
Author: Conlon, Megan ; Poltorack, Carson D ; Forcina, Giovanni C ; Armenta, David A ; Mallais, Melodie ; Perez, Marcos A ; Wells, Alex ; Kahanu, Alexis ; Magtanong, Leslie ; Watts, Jennifer L ; Pratt, Derek A ; Dixon, Scott J
Subjects: Amino acids ; Amino Acids - metabolism ; Animals ; Antioxidants ; Antioxidants - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Bioactive compounds ; Cell death ; Cell Death - drug effects ; Cell-Free System ; Chelation ; Ferroptosis - physiology ; Humans ; Indoles - pharmacology ; Inhibitors ; Iron ; Iron Chelating Agents - pharmacology ; Kinetics ; Metabolism ; Mortality ; Rapamycin ; Regulation ; Small Molecule Libraries ; Suppressors ; TOR protein ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; Trapping
Is Part Of: Nature chemical biology, 2021-06, Vol.17 (6), p.665-674
Description: 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.
Publisher: United States: Nature Publishing Group
Language: English
Identifier: ISSN: 1552-4450
EISSN: 1552-4469
DOI: 10.1038/s41589-021-00751-4
PMID: 33686292
Source: MEDLINE
ProQuest Central

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A compendium of kinetic modulatory profiles identifies ferroptosis regulators

The Author(s), under exclusive licence to Springer Nature America, Inc. 2021. ;ISSN: 1552-4450 ;EISSN: 1552-4469 ;DOI: 10.1038/s41589-021-00751-4 ;PMID: 33686292

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