靶向异柠檬酸脱氢酶（IDH）药物---2篇Science重磅推出（附原文）

gandanxiaoyang

0 p' _& l4 m3 w& W

5 a9 c7 J# _$ UIDH在细胞中的正常作用是促使异柠檬酸与α-酮戊二酸(aKG)相互转化，最终调控组蛋白和DNA突变。新的癌症相关突变导致该酶将aKG转变成了一种称作2HG（R-2-hydroxyglutarate）的不同寻常的代谢产物。研究表明，2HG与aKG竞争，由此降低了aKG依赖性酶的活性，导致染色质高度甲基化。这种超甲基化被认为干扰了正常的细胞分化，导致未成熟细胞增殖，而引发癌症。0 k) S1 t6 C% W
4月4日，来自Agios公司的科学家和合作者们在《科学》（Science）杂志发表了两篇论文，显示了在人类原发性肿瘤模型中，该公司的IDH1和IDH2（异柠檬酸脱氢酶1和2）突变体特异性小分子抑制剂的效应。这些数据增加了大量的科学研究证据，表明靶向突变的IDH1和IDH2酶极其有望成为治疗癌症的新方法。  t! M# u& K7 N% _) p
]Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation
' e) M" s1 ^0 MFang Wang1,*, Jeremy Travins1,*, Byron DeLaBarre1,*, Virginie Penard-Lacronique2,3,4,*, Stefanie Schalm1,*, Erica Hansen1, Kimberly Straley1, Andrew Kernytsky1, Wei Liu1, Camelia Gliser1, Hua Yang1, Stefan Gross1, Erin Artin1, Veronique Saada3, Elena Mylonas2,3,4, Cyril Quivoron2,3,4, Janeta Popovici-Muller1, Jeffrey O. Saunders1,†, Francesco G. Salituro1,‡, Shunqi Yan5, Stuart Murray1, Wentao Wei6, Yi Gao7, Lenny Dang1, Marion Dorsch1, Sam Agresta1, David P. Schenkein1, Scott A. Biller1, Shinsan M. Su1, Stephane de Botton2,3,4, Katharine E. Yen1,§
. G, @, S. O  Q' u  K% |; ]A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases- 1 and -2 (IDH1, IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite R (-)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia (AML) cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.9 l5 A8 H; c! r
An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma CellsDan Rohle1,2,*, Janeta Popovici-Muller3,*, Nicolaos Palaskas1,*, Sevin Turcan1,*, Christian Grommes4, Carl Campos1, Jennifer Tsoi8, Owen Clark1, Barbara Oldrini1, Evangelia Komisopoulou8, Kaiko Kunii3, Alicia Pedraza7, Stefanie Schalm3, Lee Silverman3, Alexandra Miller4, Fang Wang3, Hua Yang3, Yue Chen3, Andrew Kernytsky3, Marc K. Rosenblum6, Wei Liu3, Scott A. Biller3, Shinsan M. Su3, Cameron W. Brennan1,7, Timothy A. Chan1,5, Thomas G. Graeber8,†, Katharine E. Yen3,†‡, Ingo K. Mellinghoff1,2,4,†‡
$ @; X; e% S. v: o  ~The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant—but not IDH1-wild-type—glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.

gandanxiaoyang

哪位战友可以提供原文？

gandanxiaoyang

另附文章全文。