51988-01-3Relevant articles and documents
Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion
Carmi, Caterina,Cavazzoni, Andrea,Vezzosi, Stefano,Bordi, Fabrizio,Vacondio, Federica,Silva, Claudia,Rivara, Silvia,Lodola, Alessio,Alfieri, Roberta R.,La Monica, Silvia,Galetti, Maricla,Ardizzoni, Andrea,Petronini, Pier Giorgio,Mor, Marco
experimental part, p. 2038 - 2050 (2010/08/20)
Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATPcompetitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)N-(4-(3-bromoanilino)quinazolin-6-yl)- 3 -(piperidin-1 -ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.
