Salicylanilides as inhibitors of the protein tyrosine kinase epidermal growth factor receptor
Salicylanilides as inhibitors of the protein tyrosine kinase epidermal growth factor receptor
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DOI：
10.1016/j.ejmech.2003.09.010
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发表时间：
2004-01-01
影响因子：
6.7
通讯作者：
Traxler, P
中科院分区：
文献类型：
--
作者：
Liechti, C;Séquin, U;Traxler, P
ATP竞争性抑制剂与EGFR蛋白酪氨酸激酶活性部位相互作用的药效团模型和4-苯胺喹唑啉的可能结合模式表明，水杨酸功能可作为嘧啶环的药效团替代。CAMM将水杨胺与有效的表皮生长因子受体酪氨酸激酶抑制剂4-[(3‘-chlorophenyl)amino]-6，7-dimethoxyquinazoline叠加，表明水杨胺应作为酪氨酸激酶抑制剂。合成了一系列水杨胺类化合物，并测定了它们对酪氨酸激酶的抑制活性。其中一些确实被证明是有效的和选择性的EGFR酪氨酸激酶抑制剂。最强的是28、16、20、6和15，IC50在23-71 NM范围内。(C)2003年爱思唯尔公司。版权所有。
A pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase and a putative binding mode of 4-anilinoquinazoline suggest that a salicylic acid function could serve as the pharmacophore replacement of a pyrimidine ring. Superpositions by CAMM of salicylanilides with the potent EGFR tyrosine kinase inhibitor 4-[(3'-chlorophenyl)amino]-6,7-dimethoxyquinazoline showed that salicylanilides should act as tyrosine kinase inhibitors. A series of salicylanilides was synthesized and their inhibitory activity against tyrosine kinases determined. Some of them indeed proved to be potent and selective EGFR tyrosine kinase inhibitors. The most potent ones being 28, 16, 20, 6, and 15, with IC50 in the 23-71 nM range. (C) 2003 Elsevier SAS. All rights reserved.