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Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-01-19 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00421 Janeta Popovici-Muller 1 , René M. Lemieux 1 , Erin Artin 1 , Jeffrey O. Saunders 1 , Francesco G. Salituro 1 , Jeremy Travins 1 , Giovanni Cianchetta 1 , Zhenwei Cai 2 , Ding Zhou 2 , Dawei Cui 2 , Ping Chen 2 , Kimberly Straley 1 , Erica Tobin 1 , Fang Wang 1 , Muriel D. David 3 , Virginie Penard-Lacronique 3 , Cyril Quivoron 3 , Véronique Saada 3 , Stéphane de Botton 3 , Stefan Gross 1 , Lenny Dang 1 , Hua Yang 1 , Luke Utley 1 , Yue Chen 1 , Hyeryun Kim 1 , Shengfang Jin 1 , Zhiwei Gu 4 , Gui Yao 4 , Zhiyong Luo 4 , Xiaobing Lv 4 , Cheng Fang 4 , Liping Yan 4 , Andrew Olaharski 1 , Lee Silverman 1 , Scott Biller 1 , Shin-San M. Su 1 , Katharine Yen 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-01-19 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00421 Janeta Popovici-Muller 1 , René M. Lemieux 1 , Erin Artin 1 , Jeffrey O. Saunders 1 , Francesco G. Salituro 1 , Jeremy Travins 1 , Giovanni Cianchetta 1 , Zhenwei Cai 2 , Ding Zhou 2 , Dawei Cui 2 , Ping Chen 2 , Kimberly Straley 1 , Erica Tobin 1 , Fang Wang 1 , Muriel D. David 3 , Virginie Penard-Lacronique 3 , Cyril Quivoron 3 , Véronique Saada 3 , Stéphane de Botton 3 , Stefan Gross 1 , Lenny Dang 1 , Hua Yang 1 , Luke Utley 1 , Yue Chen 1 , Hyeryun Kim 1 , Shengfang Jin 1 , Zhiwei Gu 4 , Gui Yao 4 , Zhiyong Luo 4 , Xiaobing Lv 4 , Cheng Fang 4 , Liping Yan 4 , Andrew Olaharski 1 , Lee Silverman 1 , Scott Biller 1 , Shin-San M. Su 1 , Katharine Yen 1
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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 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.
中文翻译：
AG-120（Ivosidenib）的发现：用于治疗IDH1突变癌症的一流突变IDH1抑制剂
代谢酶异柠檬酸脱氢酶1（IDH1）活性位点关键精氨酸残基（R132）的体细胞点突变赋予癌细胞新的功能获得，从而导致d的产生。-2-羟基戊二酸酯（2-HG），一种彗星代谢物。2-HG水平升高与表观遗传学改变和细胞分化受损有关。IDH1突变已在一系列血液系统恶性肿瘤和实体瘤中描述。在这里，我们报告发现了AG-120（ivosidenib），它是IDH1突变酶的抑制剂，该抑制剂在肿瘤模型中表现出明显的2-HG降低，并且能够影响原发性患者AML样品的离体分化。招募具有IDH1突变的癌症患者的1期临床试验的初步数据表明，AG-120具有可接受的安全性和临床活性。
更新日期：2018-01-19
中文翻译：
AG-120（Ivosidenib）的发现：用于治疗IDH1突变癌症的一流突变IDH1抑制剂
代谢酶异柠檬酸脱氢酶1（IDH1）活性位点关键精氨酸残基（R132）的体细胞点突变赋予癌细胞新的功能获得，从而导致d的产生。-2-羟基戊二酸酯（2-HG），一种彗星代谢物。2-HG水平升高与表观遗传学改变和细胞分化受损有关。IDH1突变已在一系列血液系统恶性肿瘤和实体瘤中描述。在这里，我们报告发现了AG-120（ivosidenib），它是IDH1突变酶的抑制剂，该抑制剂在肿瘤模型中表现出明显的2-HG降低，并且能够影响原发性患者AML样品的离体分化。招募具有IDH1突变的癌症患者的1期临床试验的初步数据表明，AG-120具有可接受的安全性和临床活性。
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