title: Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction.
abstract: 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.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Marcelo L
authors.initials: ML
authors.lastname: Actis
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Nigus D
authors.initials: ND
authors.lastname: Ambaye
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Evison
authors.affiliation: Protein Production Facility, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Youming
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Murugendra
authors.initials: M
authors.lastname: Vanarotti
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Ezelle T
authors.initials: ET
authors.lastname: McDonald
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Sotaro
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Protein Production Facility, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Heath
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Kodai
authors.initials: K
authors.lastname: Hara
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004259:DNA-Directed DNA Polymerase; D019008:Drug Resistance, Neoplasm; D006367:HeLa Cells; D006801:Humans; D064246:Mad2 Proteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000621443:3-((1-acetylpiperidin-4-yl)methyl)-5-(5-methylfuran-2-yl)thieno(2,3-d)pyrimidin-4(3H)-one; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; D011744:Pyrimidinones; D013876:Thiophenes; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human; D002945:Cisplatin
keywords: Chemotherapy; DNA damage response; High-throughput screening; Interstrand crosslink repair; Polζ; REV3L; REV7