Irreversible inhibitors of the erbB family of protein tyrosine kinases
Irreversible inhibitors of the erbB family of protein tyrosine kinases
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DOI：
10.1016/s0163-7258(02)00194-8
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发表时间：
2002-02-01
影响因子：
13.5
通讯作者：
Denny, WA
中科院分区：
文献类型：
--
作者：
Denny, WA
跨膜受体酪氨酸激酶的erbB家族启动了大量的细胞信号通路。它们在人类肿瘤中的过度表达与预后不良相关，已成为药物开发的重要靶点。4-苯胺喹啉类药物是这些酶，特别是erbB1（表皮生长因子受体）的有效和选择性ATP位点抑制剂。ATP位点结合的结构-活性研究是狭窄的，与同源性和晶体结构结合模型一致。苯胺3′位的小亲脂基团和喹唑啉6′或7′位的供电子基团的组合产生了极有效的（皮摩尔）可逆抑制剂，其中一些正在临床试验中。观察到erbB家族的酶含有一个独特的靠近atp结合位点的Cys残基（Cys773），促使了不可逆抑制剂的开发，最成功的是6-丙烯酰胺和相关的丁酰胺，与密切相关的可逆结合化合物相比，它们在体内的抗肿瘤活性显著提高。这两种类型的例子都在临床试验中。可逆和不可逆抑制剂与多种破坏dna的抗癌药物协同作用，这些药物的最大影响可能是在联合治疗中。(C) 2002爱思唯尔科学有限公司版权所有。
The erbB family of transmembrane receptor tyrosine kinases initiates a large number of cellular signalling pathways. Their overexpression in human tumours correlates with poor prognosis, and they have become important targets for drug development. The 4-anilinoquinazolines are potent and selective ATP site inhibitors of these enzymes, especially erbB1 (epidermal growth factor receptor). Structure-activity studies for binding at the ATP site are narrow, consistent with homology and crystal structure-binding models. Combinations of small lipophilic groups at the 3'-position of the aniline and electron-donating groups at the 6- or 7-positions of the quinazoline result in extremely potent (picomolar) reversible inhibitors, several of which are in clinical trial. Observation that the erbB family of enzymes contains a unique Cys residue (Cys773) close to the ATP-binding site prompted the development of irreversible inhibitors, the most successful being 6-acrylamides and related butynamides, which show significantly improved in vivo antitumour activity compared with closely related reversibly binding compounds, Solubilising side chains can be placed either at the terminus of the alkylating unit or at the quinazoline C-7, and examples of both types are in clinical trial. Both reversible and irreversible inhibitors synergise with a variety of DNA-damaging anticancer drugs, and it is likely that the greatest impact of these agents will be in combination therapy. (C) 2002 Elsevier Science Inc. All rights reserved.