Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
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DOI：
10.1158/0008-5472.can-16-1476
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发表时间：
2017-02-15
期刊：
影响因子：
11.2
通讯作者：
Stenmark, Pal
中科院分区：
文献类型：
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作者：
Gustafsson, Robert;Jemth, Ann-Sofie;Stenmark, Pal
为了维持它们的增殖，癌细胞依赖于一碳代谢来支持嘌呤和胸腺嘧啶的合成。事实上，在肿瘤转化过程中上调最高的酶之一是MTHFD2，它是一种线粒体亚甲基四氢叶酸脱氢酶和环水解酶，参与一碳代谢。由于MTHFD2只在胚胎发育期间正常表达，它为根除癌细胞提供了一种疾病选择性治疗靶点，同时保留了健康细胞。在这里，我们报告了第一个人MTHFD2抑制剂的合成和临床前表征。我们还揭示了MTHFD2与底物抑制剂以及辅酶NAD(+)和无机磷酸盐形成的络合物的第一晶体结构。我们的工作为继续开发用于癌症治疗的有效和选择性的MTHFD2抑制剂的结构框架提供了理论基础。(C)2017年AACR。
To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD(+) and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment. (C)2017 AACR.