title: Enhancement of the cytotoxic potential of the mixed EGFR and DNA-targeting 'combi-molecule' ZRBA1 against human solid tumour cells by a bis-quinazoline-based drug design approach.
abstract: ZRBA1 is a quinazoline-based molecule termed 'combi-molecule' designed to block the epidermal growth factor receptor (EGFR) and further degrade to FD105, an EGFR inhibitor plus a DNA-alkylating agent. To augment the potency of ZRBA1, we designed JDE52, a bistriazene that, following degradation, was 'programmed' to yield higher concentrations of the free inhibitor FD105 and a more cytotoxic bifunctional DNA-damaging species. The results indicated that JDE52 was capable of inducing significant blockade of EGFR phosphorylation, DNA strand breaks and interstrand cross-links in human cells. The fluorescent property of FD105, the secondary inhibitor that both JDE52 and ZRBA1 are capable of releasing, has permitted the analysis of its levels in tumour cells by ultraviolet flow cytometry. It was found that JDE52 was indeed capable of significantly releasing higher levels of fluorescence (P<0.05) in human tumour cells when compared with ZRBA1. Apoptosis was triggered by JDE52 at a faster rate than ZRBA1 and led to higher levels of cell killing. The results in toto suggest that the superior potency of JDE52, when compared with ZRBA1, may be imputed to mechanisms associated with the generation of higher intracellular concentrations of FD105 and to the induction of DNA cross-links. These combined mechanisms (blockade of EGFR-tyrosine kinase and induction of cross-links) contributed to an accelerated rate of apoptosis by JDE52. This study conclusively demonstrated that designing molecules as prodrugs of high levels of quinazoline inhibitors of EGFR and bifunctional DNA cross-linking species is a valid strategy to enhance the potency of mixed EGFR-DNA-targeting combi-molecules.
authors.affiliation: Cancer Drug Research Laboratory, Department of Medicine, McGill University Health Center/Royal Victoria Hospital, Division of Medical Oncology, Montreal, Quebec, Canada.
authors.forename: Sherin
authors.initials: S
authors.lastname: Al-Safadi
authors.forename: Juozas
authors.initials: J
authors.lastname: Domarkas
authors.forename: YingShan
authors.initials: Y
authors.lastname: Han
authors.forename: Fouad
authors.initials: F
authors.lastname: Brahimi
authors.forename: Bertrand J
authors.initials: BJ
authors.lastname: Jean-Claude
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D053960:DNA Breaks / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D006801:Humans; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014226:Triazenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; C574244:JDE52; D011799:Quinazolines; D014226:Triazenes; C503825:ZRBA1 compound; C512478:EGFR protein, human; D066246:ErbB Receptors