ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia
ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia
复制标题
DOI：
10.1016/j.ccell.2018.02.002
复制
发表时间：
2018-03-12
期刊：
影响因子：
50.3
通讯作者：
Buesa, Carlos
中科院分区：
文献类型：
--
作者：
Maes, Tamara;Mascaro, Cristina;Buesa, Carlos
赖氨酸特异性脱甲基酶KDM 1A是急性髓细胞白血病（AML）干细胞潜能的关键调节因子。ORY-1001是一种高度有效和选择性的KDM 1A抑制剂，可诱导H3 K4 me 2在KDM 1A靶基因上的积累、原始细胞分化和AML中白血病干细胞能力的降低。ORY-1001表现出与标准治疗药物和选择性表观遗传抑制剂的有效协同作用，减少AML异种移植模型的生长，并延长T细胞急性白血病小鼠PDX（患者来源的异种移植）模型的存活期。将基于白血病细胞系中的表达变化开发的替代药效学生物标志物转化为来自用ORY-1001治疗的患者的样品。ORY-1001是临床试验中的选择性KDM 1A抑制剂，目前正在白血病和实体瘤患者中进行评估。
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.