Multiple mechanisms of action of ZR2002 in human breast cancer cells: a novel combi-molecule designed to block signaling mediated by the ERB family of oncogenes and to damage genomic DNA

International Journal of Cancer. Journal International Du Cancer
Fouad BrahimiBertrand J Jean-Claude

Abstract

The mechanism of action of ZR2002, a chimeric amino quinazoline designed to possess mixed EGFR tyrosine kinase (TK) inhibitory and DNA targeting properties, was compared to those of ZR01, a reversible inhibitor of the same class and PD168393, a known irreversible inhibitor of EGFR. ZR2002 exhibited 4-fold stronger EGFR TK inhibitory activity than its structural homologue ZR01 but was approximately 3-fold less active than the 6-acrylamidoquinazoline PD168393. It preferentially blocked EGF and TGFalpha-induced cell growth over PDGF and serum. It also inhibited signal transduction in heregulin-stimulated breast tumour cells, indicating that it does not only block EGFR but also its closely related erbB2 gene product. In contrast to its structural homologues, ZR2002 was capable of inducing significant levels of DNA strand breaks in MDA-MB-468 cells after a short 2 hr drug exposure at a concentration as low as 10 microM. Reversibility studies using whole cell autophosphorylation and growth assays in human breast cell lines showed that in contrast to its reversible inhibitor counterpart ZR01, ZR2002 induced irreversible inhibition of EGF-stimulated autophosphorylation in MDA-MB-468 cells and irreversible inhibition of cell growth. Mor...Continue Reading

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Citations

Jul 8, 2009·Anti-cancer Drugs·Mitra HeraviThierry M Muanza
Aug 21, 2013·Cancer Chemotherapy and Pharmacology·Rosalba D'AlessandroBrian I Carr
Feb 3, 2005·Bioorganic & Medicinal Chemistry Letters·Zakaria RachidBertrand Jacques Jean-Claude
Mar 7, 2017·Future Medicinal Chemistry·Guohui SunRugang Zhong
Mar 30, 2010·The Journal of Pharmacology and Experimental Therapeutics·Ranjita BanerjeeBertrand J Jean-Claude
Jan 26, 2018·Expert Opinion on Therapeutic Patents·Abdul HameedKhalid Mohammed Khan
Jan 4, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Qiyu QiuBertrand J Jean-Claude
Feb 19, 2008·Molecular Cancer Therapeutics·Andrea CavazzoniPier Giorgio Petronini
Feb 16, 2017·ACS Medicinal Chemistry Letters·Yameng WangRugang Zhong
Dec 13, 2006·Journal of Medicinal Chemistry·Aldo AndreaniMark W Kunkel

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