Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers.
Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers.
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DOI：
10.1021/acsmedchemlett.7b00421
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发表时间：
2018-04-12
影响因子：
4.2
通讯作者：
Yen K
中科院分区：
文献类型：
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作者：
Popovici-Muller J;Lemieux RM;Artin E;Saunders JO;Salituro FG;Travins J;Cianchetta G;Cai Z;Zhou D;Cui D;Chen P;Straley K;Tobin E;Wang F;David MD;Penard-Lacronique V;Quivoron C;Saada V;de Botton S;Gross S;Dang L;Yang H;Utley L;Chen Y;Kim H;Jin S;Gu Z;Yao G;Luo Z;Lv X;Fang C;Yan L;Olaharski A;Silverman L;Biller S;Su SM;Yen K
代谢酶异柠檬酸脱氢酶1（IDH 1）活性位点内关键精氨酸残基（R132）的体细胞点突变赋予癌细胞新的功能增益，导致产生癌代谢物d-2-羟基戊二酸（2-HG）。升高的2-HG水平与表观遗传改变和受损的细胞分化有关。IDH 1突变已在一系列血液恶性肿瘤和实体瘤中描述。在这里，我们报告了AG-120（ivosidenib）的发现，AG-120是IDH 1突变酶的抑制剂，其在肿瘤模型中表现出显著的2-HG降低，并且能够影响原代患者AML样品的离体分化。来自招募携带IDH 1突变的癌症患者的I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。
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.
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影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
1.8
作者：
Gao, Y. -D.;Olson, S. H.;Mosley, R. T.
通讯作者：
Mosley, R. T.
DOI：
10.1146/annurev-cancerbio-050216-122051
发表时间：
2017-01-01
期刊：
ANNUAL REVIEW OF CANCER BIOLOGY, VOL 1
影响因子：
--
作者：
Stein, Eytan;Yen, Katharine
通讯作者：
Yen, Katharine