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

Hendricks, J. M.; Doubravsky, C.; Wehri, E.; Li, Z.; Roberts, M. A.; Deol, K.; Lange, M.; Lasheras-Otero, I.; Dixon, S. J.; Bersuker, K.; Schaletzky, J.; Olzmann, J. A.

doi:10.1101/2022.12.14.520445

bioRxiv · 10.1101/2022.12.14.520445

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

Hendricks, J. M.·Doubravsky, C.·Wehri, E.·Li, Z.·Roberts, M. A.·Deol, K.·Lange, M.·Lasheras-Otero, I.·Dixon, S. J.·Bersuker, K.·Schaletzky, J.·Olzmann, J. A.

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Abstract

Ferroptosis is a regulated form of cell death associated with the iron-dependent accumulation of lipid peroxides. 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. Exploiting 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 inducers.

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Hendricks, J. M., Doubravsky, C., Wehri, E., Li, Z., Roberts, M. A., Deol, K., Lange, M., Lasheras-Otero, I., Dixon, S. J., Bersuker, K., Schaletzky, J., Olzmann, J. A.. 2022-12-14. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. https://doi.org/10.1101/2022.12.14.520445

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