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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Differentiation / drug effects*
  • Cell Line, Tumor / metabolism
  • Disease Models, Animal
  • Histone Demethylases / antagonists & inhibitors
  • Histone Demethylases / drug effects*
  • Histone Demethylases / genetics
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Stem Cells / drug effects
  • Stem Cells / metabolism

Substances

  • Histone Demethylases
  • KDM1A protein, human