ACF-01

ACF-01 is a first-in-class small-molecule activator of Prolyl Hydroxylase Domain Protein 2 (PHD2) being developed for the treatment of non-small cell lung cancer (NSCLC). By activating PHD2, ACF-01 promotes the hydroxylation and subsequent proteasomal degradation of Hypoxia-Inducible Factor-1α (HIF-1α), a key driver of metabolic adaptation and therapeutic resistance under hypoxic conditions. Preclinical evidence suggests that ACF-01 can restore sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, by disrupting HIF-1α-mediated glycolytic signaling and reducing ABC transporter-mediated drug efflux. In vivo studies in HCC827 xenograft models have shown that the combination of ACF-01 and osimertinib leads to significant tumor regression compared to monotherapy, with a favorable safety profile and high metabolic stability.