Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.
Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.
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DOI：
10.1021/acs.jmedchem.5b00684
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发表时间：
2015-09-10
影响因子：
7.3
通讯作者：
Song Y
中科院分区：
文献类型：
--
作者：
Wu F;Jiang H;Zheng B;Kogiso M;Yao Y;Zhou C;Li XN;Song Y
在某些癌症（例如glioma）中，在R132处的异位酸盐脱氢酶1（IDH1）的体躯体突变，而R132H和R132C突变蛋白可以降低α-酮酸（α-KGG）酸（α-kg），而D2-2-HYDRARIS r.g the the the type the the则可以减少R132H和R132C突变蛋白的活性。 G抑制许多α-KG依赖性双加氧酶，包括组蛋白脱甲基酶，引起广泛的组蛋白这些异常的表观遗传变化是造成这些癌症的原因。报告了两种抑制剂，显示其抑制剂蛋白相互作用。
Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce α-ketoglutaric acid (α-KG) to D-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many α-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for initiation of these cancers. We report the synthesis, structure activity relationships, enzyme kinetics and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.