Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents.

摘要: Abnormal cell signal transduction arising from protein tyrosine kinases has been implicated in the initiation and progression of a variety human cancers. Over past 2 decades pharmaceutical university laboratories have involved tremendous effort to develop compounds that can selectively modulate these abnormal signalling pathways. Targeting receptor kinases, especially epidermal growth factor subfamily, at forefront this as result strong clinical data correlating over-expression receptors with more aggressive There are strategies under development for inhibiting kinase activity receptors, targeting both extracellular intracellular domains. Antibody-based approaches, immunotoxins ligand-binding cytotoxic agents use domain targeted tumour therapy. Small molecule inhibitors target catalytic region by interfering ATP binding, while nonphosphorylatable peptides aimed substrate binding region. Compounds inhibit subsequent downstream signals interrupting recognition sequences also being investigated. In 5 years enormous progress made developing inhibitor sufficient potency, bioavailability selectivity against subfamily kinases. The anti-HER2 monoclonal antibody, trastuzumab, patients metastatic breast cancer is first gain FDA approval. However, preclinical trials ongoing other antibodies, immu-notoxins, small quinazoline pyrimidine-based inhibitors. Although their cytostatic potential proven, they not likely replace standard chemotherapy regimens single-agent, first-line therapeutics. Instead, promising additive synergistic antitumour effects combination chemotherapeutics suggest novel will find greatest utility efficacy conjunction existing anticancer agents.