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

✍ Scribed by Alexander J. Bridges; Donna R. Cody; Hairong Zhou; Amy McMichael; David W. Fry

Publisher
Elsevier Science
Year
1995
Tongue
English
Weight
523 KB
Volume
3
Category
Article
ISSN
0968-0896

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✦ Synopsis

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.

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