SPECIFIC-INHIBITION OF EPIDERMAL GROWTH-FACTOR RECEPTOR TYROSINE KINASE BY 4-ANILINOQUINAZOLINES

Since the mitogenic action of EGF is mediated by ligand-induced autoph osphorylation of the EGF receptor (EGFR), and EGFR is commonly overexp ressed in solid human tumours, inhibitors of receptor tyrosine kinase activity (RTK) could prove to be effective antitumour agents. Screenin g of a compound library using an EGF-RTK enzyme prepared from human tu mour derived A431 cells identified a series of potent (IC50 < 1 mu M) enzyme inhibitors. These inhibitors are quinazolines bearing a variety of substituted anilines at the 4-position. The most potent 4-anilinoq uinazolines (IC50 congruent to 20 nM) have small non-polar meta substi tuents on the aniline ring, and are competitive with ATP and non-compe titive with substrate. The growth inhibitory activity of these agents was assessed in vitro using KB cells (human oral squamous tumour) grow n in the absence or presence of EGF. A selected compound, 4-(3-chloroa nilino)quinazoline (CAQ), inhibited EGF-stimulated growth in a concent ration dependent manner and complete blockade was observed at concentr ations (1-10 mu M) which had no effect on basal growth. Selectivity of growth inhibition by CAQ was further exemplified in IGF1-stimulated K B cells where no effect was detected at concentrations which completel y blocked EGF-stimulated growth. Similarly, CAQ blocked TGF alpha-stim ulated growth in MCF-7 human breast cancer cells without affecting ins ulin-stimulated growth. These studies define a novel class of EGF-RTK inhibitors which are also potent and selective inhibitors of EGF-stimu lated human tumour cell growth in vitro.