Tyrosine kinase inhibitors .8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor
Tyrosine kinase inhibitors .8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor
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DOI：
10.1021/jm9503613
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发表时间：
1996-01-05
影响因子：
7.3
通讯作者：
Denny, WA
中科院分区：
文献类型：
--
作者：
Bridges, AJ;Zhou, H;Denny, WA
4-（3-溴苯胺基）-6，7-二甲氧基喹唑啉（32，PD 153035）是表皮生长因子受体（EGFR）酪氨酸激酶活性的强效抑制剂（IC 50 0.025 nM），在ATP位点竞争性结合。32的紧密类似物的结构-活性关系非常陡峭。一些衍生物的IC（50）的高达80倍，比从简单的加性结合能参数预测，但类似物具有类似的苯基和喹唑啉取代基的组合不显示这种“超加性”的效果。由于某些本身轻度失活的取代基在正确组合使用时可以强烈活化，因此提出某些取代的类似物在结合时具有诱导受体构象变化的能力。在喹唑啉的6-和7-位的取代存在一定的本体耐受性，因此32不是诱导构象的最佳抑制剂。二乙氧基衍生物56 [4-（3-溴苯胺基）-6，7-二乙氧基喹唑啉]显示出0.006 nM的IC 50，使其成为迄今报道的EGFR酪氨酸激酶活性的最有效抑制剂。
4-(3-Bromoanilino)-6,7-dimethoxyquinazoline (32, PD 153035) is a very potent inhibitor (IC50 0.025 nM) of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), binding competitively at the ATP site. Structure-activity relationships for close analogues of 32 are very steep. Some derivatives have IC(50)s UP to 80-fold better than predicted from simple additive binding energy arguments, yet analogues possessing combinations of similar phenyl and quinazoline substituents do not show this ''supra-additive'' effect. Because some substituents which are mildly deactivating by themselves can be strongly activating when used in the correct combinations, it is proposed that certain substituted analogues possess the ability to induce a change in the conformation of the receptor when they bind. There is some bulk tolerance for substitution in the 6- and 7-positions of the quinazoline, so that 32 is not the optimal inhibitor for the induced conformation. The 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.