title: SCR7 is neither a selective nor a potent inhibitor of human DNA ligase IV.
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.
authors.affiliation: Department of Chemistry, Goucher College, Baltimore, MD, United States.
authors.forename: George E
authors.initials: GE
authors.lastname: Greco
authors.affiliation: Departments of Internal Medicine and Molecular Genetics and Microbiology, and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM 87131, United States.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Departments of Internal Medicine and Molecular Genetics and Microbiology, and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM 87131, United States.
authors.forename: Rhys C
authors.initials: RC
authors.lastname: Brooks
authors.affiliation: Departments of Pathology, Biochemistry and Molecular Biology, Biological Sciences, and Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, CA, United States.
authors.forename: Zhengfei
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Departments of Pathology, Biochemistry and Molecular Biology, Biological Sciences, and Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, CA, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lieber
authors.affiliation: Departments of Internal Medicine and Molecular Genetics and Microbiology, and University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM 87131, United States. Electronic address: atomkinson@salud.unm.edu.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Tomkinson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000187:drug effects; D000072481:DNA Ligase ATP / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012545:Schiff Bases / Q000138:chemical synthesis / Q000494:pharmacology*; D013379:Substrate Specificity; D047368:Tumor Burden / Q000187:drug effects; D060152:V(D)J Recombination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C578537:5,6-bis(benzylideneamino)-2-mercaptopyrimidin-4-ol; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000607893:LIG4 protein, human; D011743:Pyrimidines; D011994:Recombinant Proteins; D012545:Schiff Bases; D004247:DNA; D000072481:DNA Ligase ATP
keywords: DNA double strand break repair; DNA ligase inhibitors; Human DNA ligases; Non-homologous end-joining