title: Positional isomerization of a non-cleavable combi-molecule dramatically altered tumor cell response profile.
abstract: To potentiate the quinazoline-based inhibitor of the epidermal growth factor receptor (EGFR), a chloroethyl alkylating moiety was appended to its 6-position. This led to molecules with extremely strong EGFR inhibitory potency and anomalously strong DNA-damaging potential. To assess the role of the chloroethyl group on potency, we designed a molecule in which it is shifted to the 7-position where it would be less reactive and away from the cys773 of the EGFR ATP site. The results showed that (i) ZR2009 was 10-fold less potent than its positional isomer ZR2003 in EGFR tyrosine kinase inhibition, (ii) it consistently exhibited significantly weaker antiproliferative potency than ZR2003, (iii) in reversibility assays, while ZR2003 induced sustained inhibition of EGFR phosphorylation, ZR2009 inhibitory activity was partially reversed, and (iv) likewise, ZR2009 significantly lost its activity in short exposure growth inhibitory assays and induced lower levels of DNA damage than ZR2003. Molecular modeling suggested that while the chloroethylamino group in ZR2003 was at 3.5 Å away from Cys773, that of ZR2009 was at 6.3 Å. The results in toto suggest that, while the chloroethyl is a strong alkylating group, its appendage to the 6-position is optimal for DNA damage, sustained EGFR, and growth inhibition.
authors.affiliation: Cancer Drug Research Laboratory, Department of Medicine, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC, H3A 1A1, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Rachid
authors.forename: Lisa
authors.initials: L
authors.lastname: Peyrard
authors.forename: Zhor
authors.initials: Z
authors.lastname: Senhaji Mouhri
authors.forename: Christopher
authors.initials: C
authors.lastname: Williams
authors.forename: Bertrand J
authors.initials: BJ
authors.lastname: Jean-Claude
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009588:Nitrogen Mustard Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D011799:Quinazolines; C570100:ZR 2003; D066246:ErbB Receptors
keywords: DNA alkylation; DNA damage; EGFR signaling; combi-molecule; quinazoline