SYNTHESIS AND BIOLOGICAL EVALUATION OF A SERIES OF HYDROXYBENZYLPHENYLAMINE DERIVATIVES AS INHIBITORS OF EGF RECEPTOR-ASSOCIATED TYROSINE KINASE-ACTIVITY

In order to obtain non-degradable and more potent protein-tyrosine kin ase inhibitors, derived from the 5-(2,5-dihydroxybenzyl)-aminosalicyla tes already described, we have developed a new series of 5-(2,5-dihydr oxybenzyl)phenylamines. The compounds, diversely substituted on the ph enyl ring by alcohol, nitrile, ether, ketone, amide and thioamide grou ps, were tested for their ability to inhibit epidermal growth factor ( EGF) receptor-associated tyrosine kinase activity in vitro. They inhib it the phosphorylation of the peptide substrate RR-Src by the EGF rece ptor purified from ER 22 cells, with IC50 values in the range 0.02-0.4 5 mu M. Several of these compounds inhibit EGF-dependent DNA synthesis in ER 22 cells with IC50 values of around 1 mu M and furthermore thei r inhibition has been found to be specific for various protein kinases .