1. Academic Validation
  2. A compendium of kinetic modulatory profiles identifies ferroptosis regulators

A compendium of kinetic modulatory profiles identifies ferroptosis regulators

  • Nat Chem Biol. 2021 Jun;17(6):665-674. doi: 10.1038/s41589-021-00751-4.
Megan Conlon  # 1 Carson D Poltorack  # 1 Giovanni C Forcina  # 1 David A Armenta 1 Melodie Mallais 2 Marcos A Perez 3 Alex Wells 1 Alexis Kahanu 1 Leslie Magtanong 1 Jennifer L Watts 3 Derek A Pratt 2 Scott J Dixon 4
Affiliations

Affiliations

  • 1 Department of Biology, Stanford University, Stanford, CA, USA.
  • 2 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, Canada.
  • 3 School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, WA, USA.
  • 4 Department of Biology, Stanford University, Stanford, CA, USA. sjdixon@stanford.edu.
  • # Contributed equally.
Abstract

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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