The rationale and strategy used to develop a series of highly potent, irreversible, inhibitors of the epidermal growth factor receptor family of tyrosine kinases.
The rationale and strategy used to develop a series of highly potent, irreversible, inhibitors of the epidermal growth factor receptor family of tyrosine kinases.
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DOI：
10.1002/chin.199946291
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发表时间：
1999-09
影响因子：
4.1
通讯作者：
A. Bridges
中科院分区：
文献类型：
--
作者：
A. Bridges
表皮生长因子受体 (EGFr) 是最早发现的癌基因之一，它或其配体表皮生长因子 (EGF) 和转化生长因子 a (TGFa) 在大多数临床肿瘤中过度表达。由于 EGF 和 TGFa 是有效的有丝分裂原，因此抑制 EGFr 信号传导似乎是一种可行的抗增殖策略。筛选发现了几类 EGFr 抑制剂，其中一类是二氢吲哚硫酮。与其他第一代酪氨酸激酶 (TK) 抑制剂相同，SAR 平坦且效力较差。在硫醇存在下进行重新筛选，以去除化学反应性物质，仅鉴定出两种先导物：吡啶并嘧啶和喹唑啉。这些被开发成一类非常广泛的 EGFr 抑制剂，对 EGFr 具有很大的效力和选择性，但理化性质较差，并且体内抗肿瘤活性很少（如果有的话）。与此同时，EGFr TK 家族其他成员在肿瘤发生中的复杂作用变得越来越明显，表明整个 EGFr 家族应该受到抑制。寻找具有可接受的药代动力学的有效化合物的困难也表明 TK 的不可逆抑制剂可能会产生更好的体内特性。模型表明，不寻常的 Cys773 残基可能来自喹唑啉和吡啶并嘧啶抑制剂的 6/7 位。这些位置上带有丙烯酰胺的抑制剂被证明是 EGFr 和 erbB-2 的不可逆烷化剂，具有低纳摩尔范围的细胞抑制活性和非常有效的体内抗肿瘤活性。优化的抑制剂具有异常有效的口服抗肿瘤活性，且细胞毒性可忽略不计。
The Epidermal Growth Factor receptor (EGFr) was one of the first oncogenes identified, and it, or its ligands Epidermal Growth Factor (EGF) and Transforming Growth Factor a (TGFa) are overexpressed in most clinical tumours. As EGF and TGFa are potent mitogens, it appeared that inhibition of EGFr signaling would be a viable anti-proliferative strategy. Screening found several classes of EGFr inhibitor, one of which, the indolinethiones was developed. The SAR, in common with that of other first generation tyrosine kinase (TK) inhibitors was flat, and potency was poor. Rescreening in presence of a thiol, to remove chemically reactive species, identified only two leads, a pyridopyrimidine and a quinazoline. These were developed into a very broad class of EGFr inhibitors, with great potency and selectivity for EGFr, but poor physicochemical properties, and little if any in vivo anti-tumour activity. Meanwhile the complex role of other members of the EGFr TK family in oncogenesis, was becoming apparent, suggesting that the whole EGFr family should be inhibited. The difficulty of finding potent compounds with acceptable pharmacokinetics also suggested that irreversible inhibitors of the TK might produce better in vivo profiles. Modeling suggested that the unusual Cys773 residue might be reached from the 6/7-positions of quinazoline and pyridopyrimidine inhibitors. Inhibitors with acrylamides at these positions proved to be irreversible alkylating agents for both EGFr and erbB-2 with cellular inhibitory activities in the low nanomolar range, and very potent in vivo antitumour activity. Optimized inhibitors had exceptionally potent oral antitumour activity, with negligible cytotoxicity.