AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
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DOI：
10.1158/2159-8290.cd-16-1034
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发表时间：
2017-05-01
期刊：
影响因子：
28.2
通讯作者：
Su, Shin-San Michael
中科院分区：
文献类型：
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作者：
Yen, Katharine;Travins, Jeremy;Su, Shin-San Michael
异柠檬酸脱氢酶（IDH）1和2的体细胞功能获得性突变见于多种血液肿瘤和实体瘤，导致癌代谢产物（R）-2-羟基戊二酸（2 HG）蓄积。2 HG竞争性抑制α-酮戊二酸依赖性双加氧酶，包括组蛋白脱甲基酶和泰特家族的甲基胞嘧啶双加氧酶，导致表观遗传失调和细胞分化阻滞。体外研究已经提供了突变体IDH抑制作为治疗方法的概念证明。我们报告了AG-221的发现和表征，AG-221是一种口服的、选择性的、有效的突变IDH 2酶抑制剂。AG-221在离体和异种移植小鼠模型中抑制2 HG产生并诱导原代人IDH 2突变阳性急性髓性白血病（AML）细胞的细胞分化。AG-221还在侵袭性IDH 2（R140 Q）突变AML异种移植小鼠模型中提供了统计学显著的存活益处。这些发现支持了AG-221在IDH 2突变阳性晚期血液系统恶性肿瘤患者中正在进行的临床试验的启动。意义：IDH 1/2突变在大约20%的AML患者中被鉴定，并通过阻断造血细胞分化而导致白血病。我们已经证明，靶向抑制剂AG-221在多个临床前模型中抑制突变IDH 2酶，并诱导恶性母细胞分化，支持其临床开发。(C)2017年AACR。
Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2(R140Q)-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies.SIGNIFICANCE: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. (C) 2017 AACR.