Structure-activity relationships for 4-anilinoquinazolines as potent inhibitors at the ATP binding site of the epidermal growth factor receptor in vitro.

1. Structure-activity relationships are described for the inhibition of the tyrosine kinase activity (phosphorylation of a fragment of phospholipase Cg1) of the epidermal growth factor receptor (EGFR) by 4-anilinoquinazolines. These compounds are competitive inhibitors at the ATP binding site. 2. The preferred side chain is anilino-, substituted at the 3-position with small lipophilic groups. The quinazoline moiety is absolutely required for activity, but substituents on the quinazoline greatly modulate potency, with electron-donating groups favoured. The most potent analogue, the 6,7-dimethoxy derivative (compound 20), has an IC50 of 29 pmol/L and a very high selectivity for the EGFR over other tyrosine kinase enzymes. 3. The present study shows that it is possible to identify small molecules that are very potent, yet highly selective, inhibitors of a single component of the growth signal transduction pathway in cells.