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Title: SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV.

Authors: Greco, George E; Matsumoto, Yoshihiro; Brooks, Rhys C; Lu, Zhengfei; Lieber, Michael R; Tomkinson, Alan E

Published In DNA Repair (Amst), (2016 07)

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.

PubMed ID: 27235626 Exiting the NIEHS site

MeSH Terms: Animals; Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/pharmacology*; Cell Line, Tumor; Cell Survival/drug effects; DNA Breaks, Double-Stranded; DNA End-Joining Repair/drug effects; DNA Ligase ATP/antagonists & inhibitors; DNA Ligase ATP/genetics*; DNA Ligase ATP/metabolism; DNA/genetics*; DNA/metabolism; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/pharmacology*; Epithelial Cells/drug effects; Epithelial Cells/metabolism; Epithelial Cells/pathology; Escherichia coli/genetics; Escherichia coli/metabolism; Gene Expression; Humans; Leukocytes/drug effects; Leukocytes/metabolism; Leukocytes/pathology; Mice; Neurons/drug effects; Neurons/metabolism; Neurons/pathology; Pyrimidines/chemical synthesis; Pyrimidines/pharmacology*; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Schiff Bases/chemical synthesis; Schiff Bases/pharmacology*; Substrate Specificity; Tumor Burden/drug effects; V(D)J Recombination/drug effects; Xenograft Model Antitumor Assays

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