title: Novel nitrogen mustard-armed combi-molecules for the selective targeting of epidermal growth factor receptor overexperessing solid tumors: discovery of an unusual structure-activity relationship.
abstract: To enhance the potency of "combi-molecules", we designed 6a-d and 18 to release an inhibitor of EGFR TK and a bifunctional alkylator. The combi-molecules blocked EGFR TK with potency increasing with the basicity of the mustard moiety. They selectively killed cells transfected with EGFR and were potent against the DU145 prostate cancer cells. Combi-molecule 6a blocked EGFR phosphorylation in an irreversible manner, induced DNA-cross-links, and arrested the cells in mid-S.
authors.affiliation: Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, Montreal, H3A 1A1, Quebec, Canada.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Rachid
authors.forename: Fouad
authors.initials: F
authors.lastname: Brahimi
authors.forename: Qiyu
authors.initials: Q
authors.lastname: Qiu
authors.forename: Christopher
authors.initials: C
authors.lastname: Williams
authors.forename: Janet M
authors.initials: JM
authors.lastname: Hartley
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Bertrand J
authors.initials: BJ
authors.lastname: Jean-Claude
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014162:Transfection; D014226:Triazenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D009588:Nitrogen Mustard Compounds; D014226:Triazenes; D004247:DNA; D066246:ErbB Receptors