Discovery of Novel Quinazoline-Based KDM1A Inhibitors as Dual Inducers of Ferroptosis and Apoptosis in Esophageal Cancer

Abstract Lysine-specific demethylase 1 (KDM1A) is an FAD-dependent epigenetic target implicated in cancer progression. Starting from lead compound ZY-1 (IC50 = 105 nM), we designed a series of quinazoline-based reversible KDM1A inhibitors via a functional group migration strategy. Structure−activity relationship studies (SARs) identified JH-1 as the most potent analogue, with an IC50 of 35 nM. JH-1 selectively binds KDM1A, inhibits H3K4me1/2 demethylation, and induces both ferroptosis (lipid ROS accumulation) and apoptosis in esophageal cancer cells. In a KYSE510 xenograft model, oral administration of JH-1 significantly suppressed tumor growth without obvious toxicity. These results establish JH-1 as a promising reversible KDM1A inhibitor and validate the quinazoline scaffold for epigenetic cancer therapy.