ChemBio seminar by Prof. Derek Pratt (Uni Ottawa) - CH-635
Event details
| Date | 25.06.2024 |
| Hour | 10:45 › 11:45 |
| Speaker | Prof. Derek Pratt |
| Location | |
| Category | Conferences - Seminars |
| Event Language | English |
Title: The Chemical Basis of Ferroptosis, Development of Tools to Study it and Design of Compounds to Inhibit it
Abstract:
The accumulation of oxidized lipids has long been implicated in a vast array of diseases, but has more recently been shown to drive a specific type of cell death called ferroptosis. Over the years, we have worked to elucidate the molecular mechanisms of the archetype ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1,[1] and delineate the roles of enzyme-mediated and spontaneous lipid peroxidation on the initiation and propagation of ferroptosis.[2] In this lecture we will recount these advances, which were enabled by the concepts and tools of physical organic chemistry, and that lead to the development of high-throughput methods to monitor phospholipid peroxidation in model membranes and mammalian cells, including the FENIX (Fluoresence-ENabled Inhibited autoXidation) assay.[3][4] We will describe how FENIX made possible the characterization of multiple endogenous ferroptosis suppression systems which either synthesize or regenerate inhibitors of lipid peroxidation,[5, 6] including ferroptosis suppressor protein-1.[7],[8] and clinical candidates for treatments of ferroptosis-driven diseases, including the metal thiosemicarbazone CuATSM.[9] Lastly we will show how we have built upon these insights to develop the most potent ferroptosis inhibitors to date,[10] which have recently been validated in vivo and now serves as promising lead compounds for therapeutic development for indications wherein ferroptosis has been implicated.
1. ACS Cent Sci 2017, 3:232–243. https://doi.org/10.1021/acscentsci.7b00028
2. ACS Cent Sci 2018, 4:387–396. https://doi.org/10.1021/acscentsci.7b00589
3. Cell Chem Biol 2019, 26:1594-1607.e7. https://doi.org/10.1016/j.chembiol.2019.09.007
4. ACS Chem Biol 2022, 18: 461-571. https://doi.org/10.1021/acschembio.2c00897
5. Nat Chem Biol 2020, 16:1351–1360. https://doi.org/10.1038/s41589-020-0613-y
6. J Am Chem Soc 2022, 144:15825–15837. https://doi.org/10.1021/jacs.2c06804
7. Nature 2019, 575:693–698. https://doi.org/10.1038/s41586-019-1707-0
8. Nature 2022, 608:778–783. https://doi.org/10.1038/s41586-022-05022-3
9. J Am Chem Soc 2021, 143:19043–19057. https://doi.org/10.1021/jacs.1c08254
10. J Am Chem Soc 2022, 144:14706–14721. https://doi.org/10.1021/jacs.2c05252
Speaker's biography:
Derek is an Ottawa native – born and raised – and attended Carleton University, from which he graduated with Highest Honours in Chemistry in 1999. A life-changing experience as an undergraduate researcher with Dr. Keith Ingold motivated Derek to pursue a career in research. Supported by a NSERC Julie Payette post-graduate scholarship, he attended Vanderbilt University for his Ph.D. studies under the supervision of Professor Ned Porter. He then carried out post-doctoral research at the University of Illinois at Urbana-Champaign with Professor Wilfred van der Donk, where he was supported by a Jane Coffin Childs Fund fellowship. Excited to return to Canada, Derek began his independent career in 2005 at Queen's University as Canada Research Chair in Free Radical Chemistry, which he renewed following his recruitment to the University of Ottawa in 2010. He was promoted to Full Professor in 2016 and became University Research Chair in Free Radical Chemistry in 2021. Among several recognitions for research excellence, Derek has been a recipient of the Keith Fagnou (2015) and Bernard Belleau (2024) awards from the Canadian Society for Chemistry and the Bessel Prize of the Alexander von Humboldt foundation (2019). In addition to his academic duties, Derek is the scientific co-founder and head of chemistry of Prothegen Inc., which develops therapeutics based on the modulation of ferroptotic cell death. Derek currently serves as a member of NSERC's Chemistry Evaluation Group and is an Associate Editor for Science Advances, the open-access extension of Science magazine.
Lab website: www.theprattgroup.org
Abstract:
The accumulation of oxidized lipids has long been implicated in a vast array of diseases, but has more recently been shown to drive a specific type of cell death called ferroptosis. Over the years, we have worked to elucidate the molecular mechanisms of the archetype ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1,[1] and delineate the roles of enzyme-mediated and spontaneous lipid peroxidation on the initiation and propagation of ferroptosis.[2] In this lecture we will recount these advances, which were enabled by the concepts and tools of physical organic chemistry, and that lead to the development of high-throughput methods to monitor phospholipid peroxidation in model membranes and mammalian cells, including the FENIX (Fluoresence-ENabled Inhibited autoXidation) assay.[3][4] We will describe how FENIX made possible the characterization of multiple endogenous ferroptosis suppression systems which either synthesize or regenerate inhibitors of lipid peroxidation,[5, 6] including ferroptosis suppressor protein-1.[7],[8] and clinical candidates for treatments of ferroptosis-driven diseases, including the metal thiosemicarbazone CuATSM.[9] Lastly we will show how we have built upon these insights to develop the most potent ferroptosis inhibitors to date,[10] which have recently been validated in vivo and now serves as promising lead compounds for therapeutic development for indications wherein ferroptosis has been implicated.
1. ACS Cent Sci 2017, 3:232–243. https://doi.org/10.1021/acscentsci.7b00028
2. ACS Cent Sci 2018, 4:387–396. https://doi.org/10.1021/acscentsci.7b00589
3. Cell Chem Biol 2019, 26:1594-1607.e7. https://doi.org/10.1016/j.chembiol.2019.09.007
4. ACS Chem Biol 2022, 18: 461-571. https://doi.org/10.1021/acschembio.2c00897
5. Nat Chem Biol 2020, 16:1351–1360. https://doi.org/10.1038/s41589-020-0613-y
6. J Am Chem Soc 2022, 144:15825–15837. https://doi.org/10.1021/jacs.2c06804
7. Nature 2019, 575:693–698. https://doi.org/10.1038/s41586-019-1707-0
8. Nature 2022, 608:778–783. https://doi.org/10.1038/s41586-022-05022-3
9. J Am Chem Soc 2021, 143:19043–19057. https://doi.org/10.1021/jacs.1c08254
10. J Am Chem Soc 2022, 144:14706–14721. https://doi.org/10.1021/jacs.2c05252
Speaker's biography:
Derek is an Ottawa native – born and raised – and attended Carleton University, from which he graduated with Highest Honours in Chemistry in 1999. A life-changing experience as an undergraduate researcher with Dr. Keith Ingold motivated Derek to pursue a career in research. Supported by a NSERC Julie Payette post-graduate scholarship, he attended Vanderbilt University for his Ph.D. studies under the supervision of Professor Ned Porter. He then carried out post-doctoral research at the University of Illinois at Urbana-Champaign with Professor Wilfred van der Donk, where he was supported by a Jane Coffin Childs Fund fellowship. Excited to return to Canada, Derek began his independent career in 2005 at Queen's University as Canada Research Chair in Free Radical Chemistry, which he renewed following his recruitment to the University of Ottawa in 2010. He was promoted to Full Professor in 2016 and became University Research Chair in Free Radical Chemistry in 2021. Among several recognitions for research excellence, Derek has been a recipient of the Keith Fagnou (2015) and Bernard Belleau (2024) awards from the Canadian Society for Chemistry and the Bessel Prize of the Alexander von Humboldt foundation (2019). In addition to his academic duties, Derek is the scientific co-founder and head of chemistry of Prothegen Inc., which develops therapeutics based on the modulation of ferroptotic cell death. Derek currently serves as a member of NSERC's Chemistry Evaluation Group and is an Associate Editor for Science Advances, the open-access extension of Science magazine.
Lab website: www.theprattgroup.org
Practical information
- Informed public
- Free