Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction.
Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction.
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DOI：
10.1016/j.bmc.2016.07.026
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发表时间：
2016-09-15
影响因子：
3.5
通讯作者：
Fujii N
中科院分区：
文献类型：
--
作者：
Actis ML;Ambaye ND;Evison BJ;Shao Y;Vanarotti M;Inoue A;McDonald ET;Kikuchi S;Heath R;Hara K;Hashimoto H;Fujii N
DNA 链间交联 (ICL) 修复 (ICLR) 与癌细胞对 ICL 诱导化疗药物的耐药性有关。尽管 ICL 诱导化疗具有临床意义，但很少有研究关注开发 ICLR 小分子抑制剂。哺乳动物 DNA 聚合酶 z 由催化亚基 REV3L 和非催化亚基 REV7 组成，是 ICLR 所必需的。为了鉴定能够通过靶向 REV7 在机制上抑制 ICLR 的小分子化合物，进行了高通量筛选和构效关系 (SAR) 分析。化合物 1 被鉴定为 REV7 与 REV3L 的 REV7 结合序列相互作用的抑制剂。在核磁共振分析中，化合物 7（化合物 1 的优化类似物）直接与 REV7 结合，并抑制在启动子和报告区域之间含有 ICL 的报告质粒的重新激活。用顺铂和化合物7处理的HeLa细胞的标准化克隆形成存活率低于仅用顺铂处理的细胞。这些发现表明 REV7/REV3L 相互作用的小分子抑制剂可以通过抑制 ICLR 使细胞化学增敏。
DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase ζ, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure-activity relationship (SAR) analysis were performed. Compound 1 was identified as an inhibitor of the interaction of REV7 with the REV7-binding sequence of REV3L. Compound 7 (an optimized analog of compound 1) bound directly to REV7 in nuclear magnetic resonance analyses, and inhibited the reactivation of a reporter plasmid containing an ICL in between the promoter and reporter regions. The normalized clonogenic survival of HeLa cells treated with cisplatin and compound 7 was lower than that for cells treated with cisplatin only. These findings indicate that a small-molecule inhibitor of the REV7/REV3L interaction can chemosensitize cells by inhibiting ICLR.
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影响因子：
5.3
作者：
Hicks, J. Kevin;Chute, Colleen L.;Canman, Christine E.
通讯作者：
Canman, Christine E.
影响因子：
2.7
作者：
Dalvit, C;Fogliatto, G;Stockman, B
通讯作者：
Stockman, B
影响因子：
4.3
作者：
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通讯作者：
Xiao, Wei
DOI：
10.1038/nrc3088
发表时间：
2011-06-24
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1107/s1744309109046181
发表时间：
2009-12-01
影响因子：
0.9
作者：
Hara, Kodai;Shimizu, Toshiyuki;Hashimoto, Hiroshi
通讯作者：
Hashimoto, Hiroshi