TY  - JOUR
A1  - Nishida Xavier da Silva, Thamara
A1  - Schulte, Clemens
A1  - Nunes Alves, Ariane
A1  - Maric, Hans Michael
A1  - Friedmann Angeli, José Pedro
T1  - Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules
T2  - Cell Death & Disease
N2  - Ferroptosis is a form of cell death characterized by phospholipid peroxidation, where numerous studies have suggested that the induction of ferroptosis is a therapeutic strategy to target therapy refractory cancer entities. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone reductase, is a key determinant of ferroptosis vulnerability, and its pharmacological inhibition was shown to strongly sensitize cancer cells to ferroptosis. A first generation of FSP1 inhibitors, exemplified by the small molecule iFSP1, has been reported; however, the molecular mechanisms underlying inhibition have not been characterized in detail. In this study, we explore the species-specific inhibition of iFSP1 on the human isoform to gain insights into its mechanism of action. Using a combination of cellular, biochemical, and computational methods, we establish a critical contribution of a species-specific aromatic architecture that is essential for target engagement. The results described here provide valuable insights for the rational development of second-generation FSP1 inhibitors combined with a tracer for screening the druggable pocket. In addition, we pose a cautionary notice for using iFSP1 in animal models, specifically murine models.
KW  - cell biology
KW  - chemical libraries
Y1  - 2023
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/35794
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-357943
VL  - 14
ER  -