SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV. Greco, G. E., Matsumoto, Y., Brooks, R. C., Lu, Z., Lieber, M. R., & Tomkinson, A. E. DNA repair, 43:18–23, 2016. doi abstract bibtex 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.
@article{greco_scr7_2016,
title = {{SCR7} is neither a selective nor a potent inhibitor of human {DNA} ligase {IV}},
volume = {43},
issn = {1568-7856},
doi = {10.1016/j.dnarep.2016.04.004},
abstract = {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.},
language = {eng},
journal = {DNA repair},
author = {Greco, George E. and Matsumoto, Yoshihiro and Brooks, Rhys C. and Lu, Zhengfei and Lieber, Michael R. and Tomkinson, Alan E.},
year = {2016},
pmid = {27235626},
pmcid = {PMC5042453},
keywords = {Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, DNA, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Ligase ATP, DNA double strand break repair, DNA ligase inhibitors, Enzyme Inhibitors, Epithelial Cells, Escherichia coli, Gene Expression, Human DNA ligases, Humans, Leukocytes, Mice, Neurons, Non-homologous end-joining, Pyrimidines, Recombinant Proteins, Schiff Bases, Substrate Specificity, Tumor Burden, V(D)J Recombination, Xenograft Model Antitumor Assays},
pages = {18--23},
}
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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.","language":"eng","journal":"DNA repair","author":[{"propositions":[],"lastnames":["Greco"],"firstnames":["George","E."],"suffixes":[]},{"propositions":[],"lastnames":["Matsumoto"],"firstnames":["Yoshihiro"],"suffixes":[]},{"propositions":[],"lastnames":["Brooks"],"firstnames":["Rhys","C."],"suffixes":[]},{"propositions":[],"lastnames":["Lu"],"firstnames":["Zhengfei"],"suffixes":[]},{"propositions":[],"lastnames":["Lieber"],"firstnames":["Michael","R."],"suffixes":[]},{"propositions":[],"lastnames":["Tomkinson"],"firstnames":["Alan","E."],"suffixes":[]}],"year":"2016","pmid":"27235626","pmcid":"PMC5042453","keywords":"Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, DNA, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Ligase ATP, DNA double strand break repair, DNA ligase inhibitors, Enzyme Inhibitors, Epithelial Cells, Escherichia coli, Gene Expression, Human DNA ligases, Humans, Leukocytes, Mice, Neurons, Non-homologous end-joining, Pyrimidines, Recombinant Proteins, Schiff Bases, Substrate Specificity, Tumor Burden, V(D)J Recombination, Xenograft Model Antitumor Assays","pages":"18–23","bibtex":"@article{greco_scr7_2016,\n\ttitle = {{SCR7} is neither a selective nor a potent inhibitor of human {DNA} ligase {IV}},\n\tvolume = {43},\n\tissn = {1568-7856},\n\tdoi = {10.1016/j.dnarep.2016.04.004},\n\tabstract = {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.},\n\tlanguage = {eng},\n\tjournal = {DNA repair},\n\tauthor = {Greco, George E. and Matsumoto, Yoshihiro and Brooks, Rhys C. and Lu, Zhengfei and Lieber, Michael R. and Tomkinson, Alan E.},\n\tyear = {2016},\n\tpmid = {27235626},\n\tpmcid = {PMC5042453},\n\tkeywords = {Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, DNA, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Ligase ATP, DNA double strand break repair, DNA ligase inhibitors, Enzyme Inhibitors, Epithelial Cells, Escherichia coli, Gene Expression, Human DNA ligases, Humans, Leukocytes, Mice, Neurons, Non-homologous end-joining, Pyrimidines, Recombinant Proteins, Schiff Bases, Substrate Specificity, Tumor Burden, V(D)J Recombination, Xenograft Model Antitumor Assays},\n\tpages = {18--23},\n}\n\n","author_short":["Greco, G. E.","Matsumoto, Y.","Brooks, R. 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