2. Academic Validation
  3. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis

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

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: jschaletzky@berkeley.edu.
  • 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: olzmann@berkeley.edu.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153629
    99.56%, FSP1 Inhibitor