Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules
Please always quote using this URN: urn:nbn:de:bvb:20-opus-357943
- 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;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.…
Author: | Thamara Nishida Xavier da Silva, Clemens Schulte, Ariane Nunes Alves, Hans Michael Maric, José Pedro Friedmann Angeli |
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URN: | urn:nbn:de:bvb:20-opus-357943 |
Document Type: | Journal article |
Faculties: | Fakultät für Biologie / Rudolf-Virchow-Zentrum |
Language: | English |
Parent Title (English): | Cell Death & Disease |
Year of Completion: | 2023 |
Volume: | 14 |
Article Number: | 281 |
Source: | Cell Death & Disease (2023) 14:281. https://doi.org/10.1038/s41419-023-05787-z |
DOI: | https://doi.org/10.1038/s41419-023-05787-z |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | cell biology; chemical libraries |
Release Date: | 2024/04/30 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |