Enantioselective inhibition of the epidermal growth factor receptor tyrosine kinase by 4-(α-phenethylamino)quinazolines

Abstract 4-Benzylaminoquinazolines can be potent reversible inhibitors of the EGFR tyrosine kinase at the ATP binding site. Examination of benzylic methylation reveals that an ( R )-methyl group is four- to six-fold activating, with an optimal K i of 630 pM for compound II. In sharp contrast, ( S )-methylation causes a > 30 to 500-fold loss of inhibitory activity, showing that the ATP-binding site of the receptor has very low tolerance for even moderate out-of-plane bulk in certain directions. It is suggested that the best of these inhibitors can induce a conformation of the kinase not available to poorer inhibitors.