Inhibition of cancer-associated mutant isocitrate dehydrogenases: synthesis, structure-activity relationship, and selective antitumor activity.
Inhibition of cancer-associated mutant isocitrate dehydrogenases: synthesis, structure-activity relationship, and selective antitumor activity.
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DOI：
10.1021/jm500660f
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发表时间：
2014-10-23
影响因子：
7.3
通讯作者：
Song Y
中科院分区：
文献类型：
--
作者：
Liu Z;Yao Y;Kogiso M;Zheng B;Deng L;Qiu JJ;Dong S;Lv H;Gallo JM;Li XN;Song Y
异柠檬酸脱氢酶1（IDH 1）的突变经常在某些癌症如神经胶质瘤中发现。与野生型（WT）IDH 1不同，突变酶催化α-酮基谷氨酸还原为d-2-羟基谷氨酸（D2 HG），导致癌症起始。几种1-羟基吡啶-2-酮化合物被鉴定为IDH 1（R132 H）的抑制剂。共合成了61个衍生物，并对其构效关系进行了研究。有效的IDH 1（R132 H）抑制剂被鉴定为Ki值低至140 nM，而它们对WT IDH 1具有弱活性或没有活性。发现所选化合物对IDH 1（R132 C）的活性与其对IDH 1（R132 H）的抑制活性以及D2 HG的细胞产生相关，R2分别为0.83和0.73。在基于细胞的模型试验中，发现几种抑制剂可透过血脑屏障，并对具有IDH 1 R132 H突变的胶质瘤细胞表现出强效和选择性活性（EC 50 = 0.26-1.8 μM）。
Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure–activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with Ki values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R2 of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood–brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26–1.8 μM) against glioma cells with the IDH1 R132H mutation.
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影响因子：
12.7
作者：
Hartmann, Christian;Meyer, Jochen;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
影响因子：
64.8
作者：
通讯作者：
--
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：
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：
4.2
作者：
Deng, Lisheng;Endo, Kiwamu;Song, Yongcheng
通讯作者：
Song, Yongcheng