These authors contributed equally to the work.
Biological Effects of AL622, a Molecule Rationally Designed to Release an EGFR and a c-Src Kinase Inhibitor
Article first published online: 25 OCT 2012
© 2012 John Wiley & Sons A/S
Chemical Biology & Drug Design
Volume 80, Issue 6, pages 981–991, December 2012
How to Cite
Larroque-Lombard, A.-L., Ning, N., Rao, S., Lauwagie, S., Halaoui, R., Coudray, L., Huang, Y. and Jean-Claude, B. J. (2012), Biological Effects of AL622, a Molecule Rationally Designed to Release an EGFR and a c-Src Kinase Inhibitor. Chemical Biology & Drug Design, 80: 981–991. doi: 10.1111/cbdd.12043
- Issue published online: 25 OCT 2012
- Article first published online: 25 OCT 2012
- Accepted manuscript online: 3 SEP 2012 10:50AM EST
- Received 29 November 2011, revised 4 July 2012 and accepted for publication 14 August 2012
- chemical biology;
- mechanism-based drug design;
- therapeutic target
In breast cancer cells expressing c-Src and EGFR, a control of one of the two oncogenes over proliferation and invasion is observed, whereas in others, the synergistic interaction between them is required for tumor progression. With the purpose of developing molecules with the highest probability for blocking the adverse effects of these two oncogenes, we designed AL622, which contains a quinazoline head targeted to EGFR and a linker that bridges it to the PP2-like structure for targeting c-Src. In case the entire molecule would not be capable of blocking c-Src, we designed AL622 to hydrolyze to an intact c-Src-targeting PP2 molecule. After confirming its binary c-Src-EGFR targeting potency of AL622, we analyzed its potency in isogenic NIH3T3 cells transfected with EGFR and HER2 and human breast cancer cells known to be dominated by c-Src function. The results showed that in EGFR/HER-2-driven cells, it was more potent than PP2 and its activity was in the same range as the latter in more c-Src-driven cells. Its ability to block motility and invasion was comparable with that of PP2 and corresponding combinations, indicating that AL622 could be a better antitumor agent in cells where c-Src and/or EGFR play a role.