Cancer Cell
Volume 33, Issue 3, 12 March 2018, Pages 495-511.e12
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Article
ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia

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Highlights

  • ORY-1001 is a highly potent and selective clinical stage KDM1A inhibitor

  • ORY-1001 induces differentiation and compromises leukemic stem cell activity in AML

  • Chemoproteomics elucidates native KDM1A complexes in AML cells

  • Gene expression profiling yields a tool for evaluation of clinical samples

Summary

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

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

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