mechanism | organic synthesis | chemical biology
Suppression of Lipid Peroxidation and Associated Oxidative Cell Death
Phospholipid peroxidation drives the cell death process known as ferroptosis, which is believed to contribute to many pathologies, including neurodegeneration and injury arising from reperfusion of ischemic tissue following stroke or organ failure. Since lipid peroxidation is a radical-mediated chain reaction, compounds that inhibit either initiation or propagation can inhibit lipid peroxidation and suppress cell death. We use our expertise in organic radical chemistry to elucidate mechanisms of ferroptosis inhibitors, and use this understanding to design, synthesize and validate new compounds with increased potency as leads to drugs for treatment of ferroptosis-associated diseases. We also work with cell biologists to understand how genes upregulated in cancer enable cells to suppress ferroptosis and proliferate despite their high O2 utilization, providing new targets for chemotherapy.
Check out some representative work from our lab:
The Radical-Trapping Antioxidant Activity of Copper and Nickel bis(Thiosemicarbazone) Complexes Underlies Their Potency as Inhibitors of Ferroptotic Cell Death
Omkar Zilka, Jia-Fei Poon & Derek A. Pratt*
Journal of the American Chemical Society 2021, 143, 19043-19057
Potent Ferroptosis Inhibitors Can Catalyze the Cross-Dismutation of Phospholipid-Derived Alkylperoxyl Radicals & Hydroperoxyl Radicals
Jia-Fei Poon, Omkar Zilka & Derek A. Pratt*
Journal of the American Chemical Society 2020, 142, 14331-14342
Metabolic Determinants of Cancer Cell Sensitivity to Distinct Modes of Ferroptosis
Mariluz Soula, Ross A. Weber, Omkar Zilka, Hanan Alwaseem, Konnor La, Henrik Molina, Javier Garcia-Bermudez,* Derek A. Pratt* & Kıvanç Birsoy*
Nature Chemical Biology 2020, 16, 1351-1360
FSP1 is a Glutathione-Independent Ferroptosis-Suppressor
Sebastian Doll, Florencio Porto Freitas, Ron Shah… Derek A. Pratt, José Pedro Friedmann Angeli,* Marcus Conrad*
Nature 2019, 575, 693-698
Beyond DPPH: Use of Fluorescence-ENabled Inhibited AutoXidation (FENIX) to Predict Oxidative Cell Death Rescue
Ron Shah, Luke Farmer, Omkar Zilka, Anthony T. M. Van Kessel &
Derek A. Pratt*
Cell Chemical Biology 2019, 26, 1594-1607
The Radical-Trapping Antioxidant Activity of Ferrostatin-1 and Liproxstatin-1 Suggests that Lipid Peroxidation (Autoxidation) Drives Ferroptotic Cell Death
Omkar Zilka, Ron Shah, Bo Li, José Pedro Friedmann Angeli, Markus Griesser, Marcus Conrad & Derek A. Pratt*
ACS Central Science 2017, 3, 232-243
