ATH434, a promising iron-targeting compound for treating iron regulation disorders

Cytotoxic accumulation of loosely bound mitochondrial Fe²⁺ is a hallmark of Friedreich’s Ataxia (FA), a rare and fatal neuromuscular disorder with limited therapeutic options. There are no clinically approved medications targeting excess Fe²⁺ associated with FA or the neurological disorders Parkinson’s disease and Multiple System Atrophy. Traditional iron-chelating drugs clinically approved for systemic iron overload that target ferritin-stored Fe³⁺ for urinary excretion demonstrated limited efficacy in FA and exacerbated ataxia. Poor treatment outcomes reflect inadequate binding to excess toxic Fe²⁺ or exceptionally high affinities (i.e. ≤10⁻³¹) for nonpathologic Fe³⁺ that disrupts intrinsic iron homeostasis. To understand previous treatment failures and identify beneficial factors for Fe²⁺-targeted therapeutics, we compared traditional Fe³⁺ chelators deferiprone (DFP) and deferasirox (DFX) with additional iron-binding compounds including ATH434, DMOG, and IOX3. ATH434 and DFX had moderate Fe²⁺ binding affinities (K_d’s of 1–4 μM), similar to endogenous iron chaperones, while the remaining had weaker divalent metal interactions. These compounds had low/moderate affinities for Fe³⁺(0.46–9.59 μM) relative to DFX and DFP. While all compounds coordinated iron using molecular oxygen and/or nitrogen ligands, thermodynamic analyses suggest ATH434 completes Fe²⁺ coordination using H₂O. ATH434 significantly stabilized bound Fe²⁺ from ligand-induced autooxidation, reducing reactive oxygen species (ROS) production, whereas DFP and DFX promoted production. The comparable affinity of ATH434 for Fe²⁺ and Fe³⁺ position it to sequester excess Fe²⁺ and facilitate drug-to-protein iron metal exchange, mimicking natural endogenous iron binding proteins, at a reduced risk of autooxidation-induced ROS generation or perturbation of cellular iron stores.