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

• Published in: Cell chemical biology Vol. 30; no. 9; pp. 1090 - 1103.e7
• Main Authors: Hendricks, Joseph M., Doubravsky, Cody E., Wehri, Eddie, Li, Zhipeng, Roberts, Melissa A., Deol, Kirandeep K., Lange, Mike, Lasheras-Otero, Irene, Momper, Jeremiah D., Dixon, Scott J., Bersuker, Kirill, Schaletzky, Julia, Olzmann, James A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 21.09.2023
• Subjects: Antioxidants - metabolism; cancer; Cell Death; coenzyme Q10; endoperoxide; Ferroptosis; FSP1; glutathione; GPX4; Humans; Lipid Peroxidation; Neoplasms - drug therapy; small molecule screen; coenzyme Q10; ferroptosis; cell death; GPX4; endoperoxide; glutathione; cancer; small molecule screen; lipid peroxidation; FSP1
• ISSN: 2451-9456; 2451-9456; 2451-9448
• DOI: 10.1016/j.chembiol.2023.04.007

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. [Display omitted] •Identification of structurally diverse small molecule inhibitors of FSP1•FSEN1 is an uncompetitive FSP1 inhibitor that sensitizes cancer cells to ferroptosis•FSEN1 synergizes with GPX4 inhibitors and endoperoxide-based ferroptosis inducers Hendricks et al. identify a set of structurally diverse small molecules that inhibit FSP1, a CoQ oxidoreductase that suppresses ferroptosis. The most potent FSP1 inhibitor, ferroptosis sensitizer 1 (FSEN1) sensitizes cancer cells to ferroptosis and synergizes with several ferroptosis inducers, including GPX4 inhibitors and endoperoxide-containing molecules such as DHA.