期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 9, 期 4, 页码 300-305出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.7b00421
关键词
isocitrate dehydrogenase; mutant IDH1; AG-120; ivosidenib; differentiation therapy; 2-hydroxyglutarate
资金
- Agios Pharmaceuticals Inc.
- French National Institute of Health (INSERM-AVIESAN)
- French National Cancer League (LNCC)
- Institut National du Cancer [INCa-DGOS-Inserm_6043, INCa 2012-1-RT- 09, INCa-DGOS_5733]
- Fondation Association pour la Recherche sur le Cancer (ARC) [SL220130607089]
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of D-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired Mutant cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据