Bridges A J, Cody D R, Zhou H, McMichael A, Fry D W
Parke-Davis Pharmaceutical Research Division, Ann Arbor, MI 48105, USA.
Bioorg Med Chem. 1995 Dec;3(12):1651-6. doi: 10.1016/0968-0896(95)00149-2.
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.
4-苄基氨基喹唑啉类化合物在ATP结合位点可成为有效的表皮生长因子受体（EGFR）酪氨酸激酶可逆抑制剂。对苄基甲基化的研究表明，（R）-甲基具有4至6倍的激活作用，化合物11的最佳抑制常数（Ki）为630皮摩尔。与之形成鲜明对比的是，（S）-甲基化导致抑制活性丧失30至500倍，这表明受体的ATP结合位点即使对于某些方向上适度的面外基团也具有极低的耐受性。有人提出，这些抑制剂中效果最佳的能够诱导激酶形成较差抑制剂无法实现的构象。
