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

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Maes T, Mascaro C, Tirapu I, Estiarte A, Ciceri F, Lunardi S, Guibourt N, Perdones A, Lufino MMP, Somervaille TCP, Wiseman DH, Duy C, Melnick A, Willekens C, Ortega A, Martinell M, Valls N, Kurz G, Fyfe M, Castro-Palomino JC, Buesa C

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

Cancer Cell. 2018 Mar 12;33(3):495-511.e12. doi: 10.1016/j.ccell.2018.02.002. Epub 2018 Mar 1.

PubMed ID
29502954 [ View in PubMed
]
Abstract

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.

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