In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site
In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site
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DOI：
10.1038/s41375-019-0582-x
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发表时间：
2020-02-01
期刊：
影响因子：
11.4
通讯作者：
Heuser, Michael
中科院分区：
文献类型：
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作者：
Chaturvedi, Anuhar;Goparaju, Ramya;Heuser, Michael
在6%的AML患者中发现异柠檬酸脱氢酶1(IDH1)突变。突变的IDH产生R-2-羟基戊二酸(R-2HG)，通过抑制表观遗传调节因子诱导组蛋白和DNA的超甲基化，从而将代谢与肿瘤的发生联系起来。本文报道了抑制突变型IDH1(IDH1mut)酶活性的抑制剂HMS-101的生化特性、体内抗白血病作用、结构结合和分子机制。IDH1mut原代AML细胞在体外可降低2-羟基戊二酸(2HG)水平并诱导髓系分化。HMS-101和突变体IDH1的共结晶表明，HMS-101与IDH1mut的活性部位结合在酶的调节片段附近，而不是其他IDH1抑制剂。在同基因突变的IDH1小鼠模型和患者来源的人AML异种移植模型中，HMS-101还抑制2HG的产生，诱导细胞分化，延长存活时间。经HMS-101处理的细胞显示分化相关转录因子CEBPA和PU.1显著上调，细胞周期调节因子Cyclin A2下降。此外，该化合物还能减弱组蛋白的高甲基化。总之，HMS-101是一种唯一的直接结合IDH1mut活性部位的抑制剂，在IDH1mut临床前模型中是活性的。
Mutations in isocitrate dehydrogenase 1 (IDH1) are found in 6% of AML patients. Mutant IDH produces R-2-hydroxyglutarate (R-2HG), which induces histone- and DNA-hypermethylation through the inhibition of epigenetic regulators, thus linking metabolism to tumorigenesis. Here we report the biochemical characterization, in vivo antileukemic effects, structural binding, and molecular mechanism of the inhibitor HMS-101, which inhibits the enzymatic activity of mutant IDH1 (IDH1mut). Treatment of IDH1mut primary AML cells reduced 2-hydroxyglutarate levels (2HG) and induced myeloid differentiation in vitro. Co-crystallization of HMS-101 and mutant IDH1 revealed that HMS-101 binds to the active site of IDH1mut in close proximity to the regulatory segment of the enzyme in contrast to other IDH1 inhibitors. HMS-101 also suppressed 2HG production, induced cellular differentiation and prolonged survival in a syngeneic mutant IDH1 mouse model and a patient-derived human AML xenograft model in vivo. Cells treated with HMS-101 showed a marked upregulation of the differentiation-associated transcription factors CEBPA and PU.1, and a decrease in cell cycle regulator cyclin A2. In addition, the compound attenuated histone hypermethylation. Together, HMS-101 is a unique inhibitor that binds to the active site of IDH1mut directly and is active in IDH1mut preclinical models.