ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia

The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors. •ORY-1001 is a highly potent and selective clinical stage KDM1A inhibitor•ORY-1001 induces differentiation and compromises leukemic stem cell activity in AML•Chemoproteomics elucidates native KDM1A complexes in AML cells•Gene expression profiling yields a tool for evaluation of clinical samples Maes et al. develop ORY-1001, a highly potent and selective inhibitor of KDM1A/LSD1. ORY-1001 induces differentiation of leukemic cells in cell lines, primary AML samples, and AML patients. ORY-1001 is able to decrease leukemic growth and prolong survival of mouse models of acute leukemia.