Dual irreversible kinase inhibitors: Quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2
| Autor: | Frank Loganzo, Charles Ingalls, Thomas Nittoli, Xingzhi Tan, M. Brawner Floyd, Heidi L. Fraser, Kinwang Cheung, Allan Wissner, Russell Dushin, Malini Ravi |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Tertiary amine Protein Conformation Stereochemistry Clinical Biochemistry Pharmaceutical Science Biochemistry Inhibitory Concentration 50 chemistry.chemical_compound Adenosine Triphosphate Growth factor receptor Drug Discovery Quinazoline Humans Epidermal growth factor receptor Protein Kinase Inhibitors Molecular Biology Reactive center Cells Cultured chemistry.chemical_classification Binding Sites Molecular Structure biology Kinase Chemistry Organic Chemistry Vascular Endothelial Growth Factor Receptor-2 ErbB Receptors Enzyme Enzyme inhibitor Quinazolines biology.protein Molecular Medicine Biological Assay |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:3635-3648 |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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