کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1363223 | 981507 | 2007 | 14 صفحه PDF | دانلود رایگان |
A series of 4-dimethylamino-but-2-enoic acid [4-(3,6-dioxo-cyclohexa-1,4-dienylamino)-7-ethoxy-quinazolin-6-yl]-amide derivatives were prepared. These compounds have two independent reactive centers and were designed to function as dual irreversible inhibitors of the kinase domains of both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes. The compounds contain a 6-(4-(dimethylamino) crotonamide) Michael acceptor group that targets Cys-773 in EGFR and a 4-(amino-[1,4]benzoquinone) moiety that targets Cys-1045 in VEGFR-2. In vitro studies indicated that most of these compounds are relatively potent inhibitors of each enzyme. These inhibitors were compared with reference compounds that lack one or both of the reactive centers. The relative dependence of the IC50 values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase.
Compounds with two independent reactive centers were designed to function as dual irreversible inhibitors of the kinase domains of EGFR and VEGFR-2 where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 11, 1 June 2007, Pages 3635–3648