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

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

Tamara Maes  1 , Cristina Mascaró  2 , Iñigo Tirapu  2 , Angels Estiarte  2 , Filippo Ciceri  2 , Serena Lunardi  2 , Nathalie Guibourt  2 , Alvaro Perdones  2 , Michele M P Lufino  2 , Tim C P Somervaille  3 , Dan H Wiseman  3 , Cihangir Duy  4 , Ari Melnick  5 , Christophe Willekens  6 , Alberto Ortega  2 , Marc Martinell  2 , Nuria Valls  2 , Guido Kurz  2 , Matthew Fyfe  2 , Julio Cesar Castro-Palomino  2 , Carlos Buesa  2
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Free article

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

Tamara Maes et al. Cancer Cell. .
Free article

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.

Keywords: KDM1A; LSD1; ORY-1001; acute myeloid leukemia; differentiation; epigenetic; histone methylation.

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