TYROSINE KINASE INHIBITORS .8. AN UNUSUALLY STEEP STRUCTURE-ACTIVITY RELATIONSHIP FOR ANALOGS OF 4-(3-BROMOANILINO)-6,7-DIMETHOXYQUINAZOLINE (PD-153035), A POTENT INHIBITOR OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR

4-(3-Bromoanilino)-6,7-dimethoxyquinazoline (32, PD 153035) is a very potent inhibitor (IC50 0.025 nM) of the tyrosine kinase activity of th e epidermal growth factor receptor (EGFR), binding competitively at th e ATP site. Structure-activity relationships for close analogues of 32 are very steep. Some derivatives have IC(50)s UP to 80-fold better th an predicted from simple additive binding energy arguments, yet analog ues possessing combinations of similar phenyl and quinazoline substitu ents do not show this ''supra-additive'' effect. Because some substitu ents which are mildly deactivating by themselves can be strongly activ ating when used in the correct combinations, it is proposed that certa in substituted analogues possess the ability to induce a change in the conformation of the receptor when they bind. There is some bulk toler ance for substitution in the 6- and 7-positions of the quinazoline, so that 32 is not the optimal inhibitor for the induced conformation. Th e diethoxy derivative 56 [4-(3-bromoanilino)-6,7-diethoxyquinazoline] shows an IC50 Of 0.006 nM, making it the most potent inhibitor of the tyrosine kinase activity of the EGFR yet reported.