TY - JOUR
T1 - ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia
AU - Maes, Tamara
AU - Mascaró, Cristina
AU - Tirapu, Iñigo
AU - Estiarte, Angels
AU - Ciceri, Filippo
AU - Lunardi, Serena
AU - Guibourt, Nathalie
AU - Perdones, Alvaro
AU - Lufino, Michele M.P.
AU - Somervaille, Tim C.P.
AU - Wiseman, Dan H.
AU - Duy, Cihangir
AU - Melnick, Ari
AU - Willekens, Christophe
AU - Ortega, Alberto
AU - Martinell, Marc
AU - Valls, Nuria
AU - Kurz, Guido
AU - Fyfe, Matthew
AU - Castro-Palomino, Julio Cesar
AU - Buesa, Carlos
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/3/12
Y1 - 2018/3/12
N2 - 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.
AB - 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.
KW - KDM1A
KW - LSD1
KW - ORY-1001
KW - acute myeloid leukemia
KW - differentiation
KW - epigenetic
KW - histone methylation
UR - https://www.scopus.com/pages/publications/85042349039
U2 - 10.1016/j.ccell.2018.02.002
DO - 10.1016/j.ccell.2018.02.002
M3 - Article
C2 - 29502954
SN - 1535-6108
VL - 33
SP - 495-511.e12
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -