Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis

  • Cell Chem Biol. 2023 May 4;S2451-9456(23)00114-9. doi: 10.1016/j.chembiol.2023.04.007.
Joseph M Hendricks  1 ,  Cody E Doubravsky  1 ,  Eddie Wehri  2 ,  Zhipeng Li  1 ,  Melissa A Roberts  1 ,  Kirandeep K Deol  1 ,  Mike Lange  1 ,  Irene Lasheras-Otero  3 ,  Jeremiah D Momper  4 ,  Scott J Dixon  5 ,  Kirill Bersuker  1 ,  Julia Schaletzky  6 ,  James A Olzmann  7
Affiliations
  • 1. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • 2. The Henry Wheeler Center for Emerging and Neglected Diseases, University of California, Berkeley, Berkeley, CA 94720, USA.
  • 3. Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain.
  • 4. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 5. Department of Biology, Stanford University, Stanford, CA 94305, USA.
  • 6. The Henry Wheeler Center for Emerging and Neglected Diseases, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: [email protected].
  • 7. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Miller Institute for Basic Research in Science, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub - San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].
PMID: 37178691 DOI: 10.1016/j.chembiol.2023.04.007
Abstract

Ferroptosis is a regulated form of cell death associated with the iron-dependent accumulation of phospholipid hydroperoxides. Inducing Ferroptosis is a promising approach to treat therapy-resistant Cancer. Ferroptosis suppressor protein 1 (FSP1) promotes Ferroptosis resistance in Cancer by generating the antioxidant form of coenzyme Q10 (CoQ). Despite the important role of FSP1, few molecular tools exist that target the CoQ-FSP1 pathway. Through a series of chemical screens, we identify several structurally diverse FSP1 inhibitors. The most potent of these compounds, Ferroptosis sensitizer 1 (FSEN1), is an uncompetitive inhibitor that acts selectively through on-target inhibition of FSP1 to sensitize Cancer cells to Ferroptosis. Furthermore, a synthetic lethality screen reveals that FSEN1 synergizes with endoperoxide-containing Ferroptosis inducers, including dihydroartemisinin, to trigger Ferroptosis. These results provide new tools that catalyze the exploration of FSP1 as a therapeutic target and highlight the value of combinatorial therapeutic regimes targeting FSP1 and additional Ferroptosis defense pathways.

Keywords
FSP1; GPX4; cancer; cell death; coenzyme Q10; endoperoxide; ferroptosis; glutathione; lipid peroxidation; small molecule screen.
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