Logarithmically growing HN5 cells were treated with 1 μmol/L inhibitor in culture media for 4 hours. (23, Receptor phosphorylation after treatment with GW572016 recovers very slowly in a manner that reflects the dissociation rate of the inhibitor from the purified enzyme. Recent structural studies of epidermal growth factor receptor (EGFR) family extracellular regions have identified an unexpected mechanism for ligand-induced receptor dimerization that has important implications for activation and inhibition of these receptors. Zeneca Limited, 1998. Equation C National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. Quinazoline Derivatives. . and PDB-1M14 as the starting coordinates. . . The hydrogen bonds between Lys721 and Glu738 in the OSI-774 structure and Lys721 and Asp831 in the GW572016 structure are indicated by dashed lines. Burguin A, Furrer D, Ouellette G, Jacob S, Diorio C, Durocher F. PLoS One. . ⇓ The root mean squared deviation in the bonds and angles of the final model were 0.007Å and 1.30°, respectively. . This site needs JavaScript to work properly. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Ferguson KM(1). the magnitude of the protein conformation differences exceeds the degree normally caused by different crystal packing interactions, (4 Thus, the inhibitor off-rate may be an important factor that affects the duration of drug activity in vivo. In contrast, enzyme activity after preincubation with GW572016 recovered very slowly suggesting that the compound had a much slower off-rate. Appl. On day 4, cells were exposed to growth medium containing 0.1% DMSO (vehicle) or to medium containing vehicle and GW572016, OSI-774, or ZD-1839 at 1 μmol/L for 4 hours. The quinazoline ring is hydrogen bonded to the hinge region between the NH2- and COOH-terminal lobes of the kinase. | , 7) Analysis of progress in the structure and function of EGFR-family and ligands. (12) American Journal of Cancer ISSN: 0099-7374. Similar experiments were conducted with ZD-1839, OSI-774, and GW572016 using EGFR, ErbB-2, and ErbB-4 (Table 1) For compounds of this sort, Kiapp estimates as determined in these studies are not appropriate evaluations of binding potency. (7 Recovery of EGFR autophosphorylation after treatment with GW572016, ZD-1839, and OSI-774. 32 Logarithmically growing HN5 cells that naturally overexpress EGFR Requests for reprints: Edgar R. Wood, Department of Assay Development and Compound Profiling, GlaxoSmithKline, Inc., Research Triangle Park, NC 27709-13398. Moreover, the structure may help shed light on previously unexplained aspects of ErbB receptor activation and selectivity of 4-anilinoquinazoline inhibitors. Pharmacol Res. The cells were lysed at various times after inhibitor washout, and EGFR was captured by immunoprecipitation.
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