SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV.
SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV.
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DOI：
10.1016/j.dnarep.2016.04.004
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发表时间：
2016-07
期刊：
影响因子：
3.8
通讯作者：
Tomkinson, Alan E.
中科院分区：
文献类型：
--
作者：
Greco, George E.;Matsumoto, Yoshihiro;Brooks, Rhys C.;Lu, Zhengfei;Lieber, Michael R.;Tomkinson, Alan E.
DNA连接酶是一种很有吸引力的治疗方法，因为它们参与了几乎所有类型的DNA损伤的修复。用基于结构的方法确定了一系列对三种人DNA连接酶具有不同选择性的DNA连接酶抑制剂，其中一种被用于抑制乳腺癌、神经母细胞瘤和白血病细胞系中α依赖的DNA连接酶III对DNA双链断裂的异常修复。Raghavan和他的同事报告了一种以前发现的DNA连接酶抑制剂的衍生物的表征，他们称之为SCR7(在我们使用SCR7的实验中称为SCR7-R)。SCR7似乎显示了对DNA连接酶IV的选择性增加，抑制了DNA连接酶IV依赖的非同源末端连接(NHEJ)途径对DSB的修复，减少了肿瘤的生长，并提高了DSB诱导的治疗方法的有效性。在尝试合成SCR7的过程中，我们遇到了合成过程中的问题，并发现其报告的结构中存在差异。我们确定了SCR7的样品和相关化合物SCR7-G的结构，这是已发表的SCR7合成过程产生的主要产物。我们还发现，SCR7-G与商业供应商(XcessBio)提供的化合物(SCR7-X)具有相同的结构。在DNA连接实验中，不同的SCR7制剂具有相似的活性，表现出比DNA连接酶IV更强的对DNA连接酶I和III的活性。此外，在基于细胞的实验中，SCR7-R未能抑制依赖DNA连接酶IV的V(D)J重组。根据我们的结果，我们得出结论，SCR7及其衍生物既不是DNA连接酶IV的选择性也不是有效的抑制剂。
DNA ligases are attractive therapeutics because of their involvement in completing the repair of almost all types of DNA damage. A series of DNA ligase inhibitors with differing selectivity for the three human DNA ligases were identified using a structure-based approach with one of these inhibitors being used to inhibit abnormal DNA ligase IIIα-dependent repair of DNA double-strand breaks (DSB)s in breast cancer, neuroblastoma and leukemia cell lines. Raghavan and colleagues reported the characterization of a derivative of one of the previously identified DNA ligase inhibitors, which they called SCR7 (designated SCR7-R in our experiments using SCR7). SCR7 appeared to show increased selectivity for DNA ligase IV, inhibit the repair of DSBs by the DNA ligase IV-dependent non-homologous end-joining (NHEJ) pathway, reduce tumor growth, and increase the efficacy of DSB-inducing therapeutic modalities in mouse xenografts. In attempting to synthesize SCR7, we encountered problems with the synthesis procedures and discovered discrepancies in its reported structure. We determined the structure of a sample of SCR7 and a related compound, SCR7-G, that is the major product generated by the published synthesis procedure for SCR7. We also found that SCR7-G has the same structure as the compound (SCR7-X) available from a commercial vendor (XcessBio). The various SCR7 preparations had similar activity in DNA ligation assay assays, exhibiting greater activity against DNA ligases I and III than DNA ligase IV. Furthermore, SCR7-R failed to inhibit DNA ligase IV-dependent V(D)J recombination in a cell-based assay. Based on our results, we conclude that SCR7 and the SCR7 derivatives are neither selective nor potent inhibitors of DNA ligase IV.
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