Enantioselective inhibition of the epidermal growth factor receptor tyrosine kinase by 4-(alpha-phenethylamino)quinazolines.
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 Ki of 630 pM for compound 11. 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.
Bridges
A J
AJ
Parke-Davis Pharmaceutical Research Division, Ann Arbor, MI 48105, USA.
Cody
D R
DR
Zhou
H
H
McMichael
A
A
Fry
D W
DW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D010455:Peptides; D011799:Quinazolines; D000255:Adenosine Triphosphate; D066246:ErbB Receptors