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

Tamara Maes, Cristina Mascaró, Iñigo Tirapu, Angels Estiarte, Filippo Ciceri, Serena Lunardi, Nathalie Guibourt, Alvaro Perdones, Michele M.P. Lufino, Tim C.P. Somervaille, Daniel Wiseman, Cihangir Duy, Ari Melnick, Christophe Willekens, Alberto Ortega, Marc Martinell, Nuria Valls, Guido Kurz, Matthew Fyfe, Julio Cesar Castro-PalominoCarlos Buesa

Research output: Contribution to journalArticlepeer-review


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. 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.

Original languageEnglish
Pages (from-to)495-511.e12
JournalCancer Cell
Issue number3
Early online date1 Mar 2018
Publication statusPublished - 2018


  • acute myeloid leukemia
  • differentiation
  • epigenetic
  • histone methylation
  • KDM1A
  • LSD1
  • ORY-1001

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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