title: Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells.
abstract: The benefit of cancer chemotherapy based on alkylating agents is limited because of the action of DNA repair enzymes, which mitigate the damage induced by these agents. The interaction between the proteins ERCC1 and XPF involves two major components of the nucleotide excision repair pathway. Here, novel inhibitors of this interaction were identified by virtual screening based on available structures with use of the National Cancer Institute diversity set and a panel of DrugBank small molecules. Subsequently, experimental validation of the in silico screening was undertaken. Top hits were evaluated on A549 and HCT116 cancer cells. In particular, the compound labeled NSC 130813 [4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2-[(4-methyl-1-piperazinyl)methyl]] was shown to act synergistically with cisplatin and mitomycin C; to increase UVC-mediated cytotoxicity; to modify DNA repair as indicated by the staining of phosphorylated H2AX; and to disrupt interaction between ERCC1 and XPF in cells. In addition, using the Biacore technique, we showed that this compound interacts with the domain of XPF responsible for interaction with ERCC1. This study shows that small molecules targeting the protein-protein interaction of ERCC1 and XPF can be developed to enhance the effects of alkylating agents on cancer cells.
authors.affiliation: Université de Lyon, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France. lars-petter.jordheim@univ-lyon1.fr
authors.forename: Lars Petter
authors.initials: LP
authors.lastname: Jordheim
authors.forename: Khaled H
authors.initials: KH
authors.lastname: Barakat
authors.forename: Laurence
authors.initials: L
authors.lastname: Heinrich-Balard
authors.forename: Eva-Laure
authors.initials: EL
authors.lastname: Matera
authors.forename: Emeline
authors.initials: E
authors.lastname: Cros-Perrial
authors.forename: Karima
authors.initials: K
authors.lastname: Bouledrak
authors.forename: Rana
authors.initials: R
authors.lastname: El Sabeh
authors.forename: Rolando
authors.initials: R
authors.lastname: Perez-Pineiro
authors.forename: David S
authors.initials: DS
authors.lastname: Wishart
authors.forename: Richard
authors.initials: R
authors.lastname: Cohen
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
authors.forename: Charles
authors.initials: C
authors.lastname: Dumontet
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004357:Drug Synergism; D004720:Endonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D054852:Small Molecule Libraries; C095888:xeroderma pigmentosum group F protein; D016685:Mitomycin; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin