Login / Signup

Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules.

Thamara Nishida Xavier da SilvaClemens SchulteAriane Nunes AlvesHans Michael MaricJosé Pedro Friedmann Angeli
Published in: Cell death & disease (2023)
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.
Keyphrases
  • cell death
  • small molecule
  • cell cycle arrest
  • climate change
  • social media
  • fatty acid
  • young adults
  • computed tomography
  • squamous cell
  • amino acid