Novel derivatives of oleic acid effectively inhibiting ferroptosis that could be used for treatment of Friedreich Ataxia, neurodegenerative diseases, and neuropsychiatric diseases.
Ferroptosis is a non-apoptotic form of cell death characterized by the iron-dependent accumulation of toxic lipid-reactive oxygen species. Ferroptosis has been suggested to be the main driver of neurological cell death in diseases such as Parkinson's disease, Alzheimer disease, and Huntington's disease as well as in neuropsychiatric conditions such as bipolar disorder, schizophrenia, and depression. In addition, previous studies from Dr. Wilson’s lab showed that Friedreich ataxia (FRDA), an inherited neurodegenerative disorder, may involve ferroptosis in its pathogenesis (Cotticelli et al., 2019). Thus, the development of novel ferroptosis inhibitors is currently considered a promising avenue for treatment of neurodegenerative and neuropsychiatric diseases.
Based on reports that oleic acid acts as a ferroptosis inhibitor, the inventors evaluated whether it, other fatty acids, and fatty acid derivatives could rescue viability in cellular models of FRDA. Thirteen new analogs were synthesized, with a focus on improving metabolic stability and improving physico-chemical properties. Several compounds were significantly more potent than oleic acid in rescuing cell viability in cells treated with ferroptosis inducers or FRDA sensitizers. The new ferroptosis inhibitors could potentially serve as a therapeutic for treatment of FRDA, as well as other diseases with implicated ferroptosis.
Protection from FAC + BSO induced toxicity in primary human FRDA fibroblasts by (R)-24 and (S)-2. (*** = p < 0.005, * = p < 0.05, by Student’s t test. CC = Carrier Control (DMSO)) (Cotticelli, M et al. ACS Chem Neurosci. 2020, 11(17):2535-2542.)
Stage of Development:
Preclinical Discovery in FRDA models
Pending provisional application
• Cotticelli, M. et al.; ACS Chem Neurosci. 2020, 11(17):2535.
• Cotticelli, M et al.; J Pharmacol Exp Ther. 2019 Apr;369(1):47.
Docket : 20-9206