title: The combi-targeting concept: evidence for the formation of a novel inhibitor in vivo.
abstract: With the purpose of developing drugs that can block multiple targets in tumor cells, molecules termed combi-molecules or TZ-I have been designed to be hydrolyzed in vitro to TZ+I, where TZ is a DNA-damaging species and I is an inhibitor of the epidermal growth factor receptor (EGFR). Using HPLC and liquid chromatography-mass spectrometry (LC-MS), we investigated the mechanism of in vivo degradation of a prototype of one such combi-molecule, ZRBA1, which when administered i.p. rapidly degraded into FD105 (Cmax=50 micromol/l, after 30 min), a 6-aminoquinazoline that was N-acetylated to give FD105Ac (IAc) (Cmax=18 micromol/l, after 4 h). A similar rate of acetylation was observed when independently synthesized FD105 was administered i.p. More importantly, the EGFR binding affinity of IAc was 3-fold greater than that of I, indicating that the latter is converted in vivo into an even more potent EGFR inhibitor. The results in toto suggest that while in vitro TZ-I is only hydrolyzed to I+TZ, further acetylation of I in vivo leads to a third component--a highly potent EGFR inhibitor with a delayed Cmax.
authors.affiliation: Cancer Drug Research Laboratory, Department of Medicine, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada.
authors.forename: Nuria
authors.initials: N
authors.lastname: Merayo
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Rachid
authors.forename: Qiyu
authors.initials: Q
authors.lastname: Qiu
authors.forename: Fouad
authors.initials: F
authors.lastname: Brahimi
authors.forename: Bertrand J
authors.initials: BJ
authors.lastname: Jean-Claude
mesh_terms: D000107:Acetylation; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D011471:Prostatic Neoplasms / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014226:Triazenes / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
chemical_list: D011799:Quinazolines; D014226:Triazenes; C503825:ZRBA1 compound; D066246:ErbB Receptors