epidermal-growth-factor and butein

In our previous study, butein, a chalcone derivative, was found to be an inhibitor of tyrosine kinases and the inhibition was ATP-competitive. In this work, chalcone and seven chalcone derivatives were used to analyse the relationship between the structure of these compounds and their inhibition of tyrosine kinase activity. Three of chalcone derivatives, including butein, marein and phloretin, were found to have an ability to inhibit the tyrosine kinase activity of epidermal growth factor receptor (EGFR) in vitro. IC(50) was 8 microM for butein, 19 microM for marein and 25 microM for phloretin. The structural characterisations of these inhibitors suggest that the hydroxylations at C4 and C4' of these molecules may be required for them to act as EGFR tyrosine kinase inhibitors. The inhibition of EGF-induced EGFR tyrosine phosphorylation by butein was also observed in human hepatocellular carcinoma HepG2 cells, while marein and phloretin were inactive at the doses tested. Molecular modelling suggests that butein, marein and phloretin can be docked into the ATP binding pocket of EGFR. Hydrogen bonds and hydrophobic interaction appear to be important in the binding of these inhibitors to EGFR.

Topics: Amino Acid Sequence; Binding Sites; Blotting, Western; Chalcone; Chalcones; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; ErbB Receptors; Models, Molecular; Molecular Sequence Data; Phloretin; Phosphodiesterase Inhibitors; Phosphorylation; Sequence Alignment; Structure-Activity Relationship

Butein, a plant polyphenol, was shown to be a specific protein tyrosine kinase inhibitor. This compound inhibited not only the epidermal growth factor (EGF)-stimulated auto-phosphotyrosine level of EGF receptor in HepG2 cells but also tyrosine-specific protein kinase activities of EGF receptor (IC50 = 65 microM) and p60c-src (IC50 = 65 microM) in vitro. The inhibition was competitive to ATP and non-competitive to the phosphate acceptor, poly (Glu, Ala, Tyr) 6:3:1 for EGF receptor tyrosine kinase. In contrast, butein non-significantly inhibited the activities of serine- and threonine-specific protein kinases, such as protein kinase C (PKC) and cAMP-dependent protein kinase (PKA).

Topics: Carcinoma, Hepatocellular; Chalcone; Chalcones; CSK Tyrosine-Protein Kinase; Cyclic AMP-Dependent Protein Kinases; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; Flavonoids; Humans; Kinetics; Molecular Structure; Phenols; Phosphorylation; Polymers; Polyphenols; Protein Kinase C; Protein-Tyrosine Kinases; Receptor Protein-Tyrosine Kinases; src-Family Kinases; Tumor Cells, Cultured