Epidermal growth factor receptor tyrosine kinase inhibitors as potential cancer chemopreventives.

摘要: Among the most important targets for chemopreventive intervention and drug development are deregulated signal transduction pathways, protein tyrosine kinases key components of these pathways. Loss kinase regulatory mechanisms has been implicated in neoplastic growth; indeed, many oncogenes code either receptor or cellular kinases. Because its deregulation cancers (bladder, breast, cervix, colon, esophagus, head neck, lung, prostate), epidermal growth factor (EGFR) selected as a potential target chemoprevention. networks redundant, selective inhibition signaling pathways activated precancerous cancerous cells should be possible. Requirements specific EGFR inhibitors include specificity EGFR, high potency, activity intact cells, vivo. Inhibition autophosphorylation is preferred, because it result total blockade pathway. Inhibitors that compete with substrate rather than at ATP-binding site also preferable, they not likely to inhibit other ATP-using enzymes. Several classes have synthesized recently, including structures such benzylidene malononitriles, dianilinophthalimides, quinazolines, pyrimidines, [(alkylamino)methyl]-acrylophenones, enollactones, dihydroxybenzylaminosalicylates, 2-thioindoles, aminoflavones, analogue-containing peptides. A possible testing strategy agents includes following steps: (a) determine inhibitory vitro; (b) evaluate selectivity (relative kinases); (c) EGFR-mediated effects cells; (d) vivo (e.g., nude mouse tumor xenografts); (e) efficacy hamster buccal pouch rat bladder).