RSL3 is the inhibitor of the glutathione (GSH) peroxidase 4, which can inhibit the cysteine/glutamate amino acid transporter system that blocks GSH synthesis with an IC50 of 100 nM.[1] [2] RSL3, that are synthetically lethal with cell lines expressing mutant HRAS and KRAS.1. Cells transformed with oncogenic RAS have increased iron content relative to their normal cell counterparts through up-regulation of transferrin receptor 1 and downregulation of ferritin heavy chain 1 and ferritin light chain.[3]

• [1]. Christina Schott et al. Oncogenic RAS Mutants Confer Resistance of RMS13 Rhabdomyosarcoma Cells to Oxidative Stress-Induced Ferroptotic Cell Death. Front Oncol. 2015, 5: 131.

  [2]. Michel Weiwer et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorganic & Medicinal Chemistry Letters 22 (2012) 1822-1826.

  [3]. Wan Seok Yang et al. Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells. Chem Biol, 2008 Mar, 15(3): 234-245.