Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target
Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target
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DOI：
10.1021/acschembio.7b00370
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发表时间：
2017-08-01
影响因子：
4
通讯作者：
Gorjanacz, Matyas
中科院分区：
文献类型：
--
作者：
Ellermann, Manuel;Eheim, Ashley;Gorjanacz, Matyas
MTH 1是一种负责净化氧化嘌呤核苷三磷酸以防止其掺入复制DNA的水解酶。文献中发表的早期工具化合物抑制MTH 1的酶活性，随后诱导癌细胞死亡;然而，最近的研究质疑了两个事件之间的联系。因此，重要的是用高质量的化学探针验证MTH 1作为癌症依赖性。在这里，我们提出了BAY-707，一种底物竞争性，高效和选择性的MTH 1抑制剂，化学上与以前发表的那些不同。尽管具有上级细胞靶点结合和药代动力学性质，但BAY-707对MTH 1的抑制导致在单一疗法或组合疗法中明显缺乏体外或体内抗癌功效。因此，我们得出结论，MTH 1是癌细胞存活的关键。
MTH1 is a hydrolase responsible for sanitization of oxidized purine nucleoside triphosphates to prevent their incorporation into replicating DNA. Early tool compounds published in the literature inhibited the enzymatic activity of MTH1 and subsequently induced cancer cell death; however recent studies have questioned the reported link between two events. Therefore, it is important to validate MTH1 as a cancer dependency with high quality chemical probes. Here, we present BAY-707, a substrate-competitive, highly potent and selective inhibitor of MTH1, chemically distinct compared to those previously published. Despite superior cellular target engagement and pharmacokinetic properties, inhibition of MTH1 with BAY-707 resulted in a clear lack of in vitro or in vivo anticancer efficacy either in mono- or in combination therapies. Therefore, we conclude that MTH1 is dispensable for cancer cell survival.