SRS11-92, a Ferrostatin-1 Analogue, is a Potent Ferroptosis Inhibitor

Ferroptosis is a type of programmed cell death and is dependent on iron and characterized by the accumulation of lipid peroxides. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways. In particular, SRS11-92 is a potent inhibitor of a variety of clinically relevant oxidative cell death phenotypes.

Ferroptosis is a form of regulated, oxidative, nonapoptotic cell death. SRS11-92 fully protects oligodendrocytes from cystine deprivation when tested at 100 nM. The ferroptosis inhibitor Moreover, SRS11-92 is efficacious in protecting human and mouse cellular models of friedreich ataxia treated with ferric ammonium citrate. Cells treated with FAC and L-buthionine (S,R)-sulfoximine (BSO) consistently show decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreases the cell death associated with frataxin knockdown in healthy human fibroblasts.

Ferroptosis associates with various diseases including acute kidney injury, cancer, and cardiovascular, neurodegenerative, and hepatic diseases. Researchers tested the efficacy of SRS11-92 at concentrations ranging from 50 μM to 5 nM in the murine I154F FRDA fibroblasts. Of these, 75% of the cells died 48 hours following treatment under the assay conditions. SRS11-92 rescues the cells completely at 500 nM. Finally, SRS11-92 is efficacious in protecting FRDA cells in primary, patient-derived fibroblasts (GM4078) treated with ferric ammonium citrate.

Taken together, these data suggest that SRS11-92 may have therapeutic potential in friedreich ataxia. In addition, SRS11-92 slows the accumulation of lipid hydroperoxides, due to inhibition of lipoxygenases. All in all, SRS11-92 inhibits oxidative lipid damage and cell death in diverse disease models.

Rachid Skouta, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. 2014 Mar 26;136(12):4551-6.