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.
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
Affiliations
  • 1. Oryzon Genomics, S.A. Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, Spain. Electronic address: [email protected].
  • 2. Oryzon Genomics, S.A. Carrer Sant Ferran 74, 08940 Cornellà de Llobregat, Spain.
  • 3. Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
  • 4. Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, 10065 NY, USA.
  • 5. Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, 10065 NY, USA; Department of Pharmacology, Weill Cornell Medicine, New York, 10065 NY, USA.
  • 6. Drug Development Department (DITEP) and Hematology Department, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France.
PMID: 29502954 DOI: 10.1016/j.ccell.2018.02.002
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.
Products