ACF-02

ACF-02 is a novel, first-in-class small molecule therapeutic candidate designed for the treatment of idiopathic pulmonary fibrosis (IPF). It functions as a redox protector for prolyl hydroxylase domain protein 2 (PHD2), an enzyme responsible for the hydroxylation and subsequent degradation of hypoxia-inducible factor-1α (HIF-1α). In fibrotic conditions, TGF-β1-induced oxidative stress leads to the production of reactive oxygen species (ROS) that oxidize the ferrous iron cofactor of PHD2. This oxidation impairs PHD2's enzymatic function, causing aberrant stabilization of HIF-1α even under normal oxygen conditions—a state defined as "oxidative hypoxia." ACF-02 binds to PHD2 and prevents this ROS-mediated oxidation of its iron center, thereby restoring appropriate HIF-1α turnover and breaking the self-sustaining NOX-ROS-HIF-1α feedback loop that drives fibroblast activation and extracellular matrix deposition. Preclinical studies in bleomycin-induced lung fibrosis models have demonstrated that ACF-02 significantly reduces fibrotic markers and improves lung architecture with superior efficacy compared to nintedanib.