对c-Met和突变型EGFR有双重抑制作用的EGFR变构抑制剂的发现、结构优化及其抗肿瘤活性的研究

获得性耐药是限制EGFR抑制剂在肺癌治疗中应用的主要瓶颈,发生机制主要为耐药突变的出现和旁路或下游信号通路的激活。前者常发生在ATP结合域，这对于现有的ATP竞争性抑制剂来说是致命的，而对变构抑制剂来说，这种突变不会影响其药效；后者主要以MET基因扩增为主，可单独发生或与耐药突变共存。基于以上，我们拟开发对c-Met和突变型EGFR均有抑制作用的EGFR变构抑制剂，它的结合位点为非ATP结合域，可避免由耐药突变引起的活性消失，故能更有效地治疗耐药性肺癌。为此，我们首先建立了相关的药效团模型，再用虚拟筛选结合活性测试的方法获得了先导物CEI-1。结构改造后得到了10个活性突出的变构抑制剂，并总结了初步构效关系。本项目拟继续设计合成100个新化合物，并进行活性评价以及作用机制的深入研究，以期获得抗耐药性更佳的EGFR变构抑制剂。通过本项目的研究，将为解决肿瘤耐药性问题提供新思路，奠定研究基础。

Aquired resistance is the bottle-neck that restricts the use of EGFR inhibitors in the treatment of lung cancers, and the main mechanisms are the emergence of resistance mutation and bypass or downstream signal pathways activation. The former usually occurrs in ATP binding domain; the latter mainly includes MET gene amplification which can occurs alone or coexists with resistance mutation. Thus, we intend to develop “EGFR allosteric inhibitors inhibiting the c-Met and mutunt EGFR simultaneously” to overecome drug-resistant lung cancers effectively. The binding site of allosteric inhibitor is not ATP binding domain, therefore the activity will not disappear although the resistance mutation occurs. Firstly, we construted the pharmacophores of c-Met and mutunt EGFR, and the leading compound CEI-1 was obtained by the methods of virtual screening and bioassays. After the optimization of its structure, ten potent allosteric inhibitors were obtained and the preliminary SARs were summarized. Based on the above, 100 novel compounds will be designed, synthesized and evaluated for their bioactivities in this project and SARs and anti-tumor mechanism will also be studied further in order to obtain EGFR allosteric inhibitors with more potent antagonizing drug-resistance. Our project will provide a novel thinking about solving the problem of drug resistance and research foundation will be established meanwhile.