BCR/ABL-HDAC双靶点抑制剂的设计、合成及生物活性研究

项目名称： BCR/ABL-HDAC双靶点抑制剂的设计、合成及生物活性研究

项目编号： No.81202410

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 朱雍

作者单位： 中国药科大学

项目金额： 23万元

中文摘要： 蛋白激酶BCR/ABL抑制剂是目前国际抗肿瘤药物研究的热点之一，虽然疗效较好，但仍存在毒副作用和耐药性等问题。多项研究表明BCR/ABL抑制剂和HDAC抑制剂具有很好的协同抗肿瘤效果。因此，开发BCR/ABL-HDAC双靶点抑制剂有望成为新一代抗肿瘤药物。本项目拟在申请者前期工作的基础上，充分考虑两类靶点抑制剂的结构特征，通过分子融合作用原理，构建双靶标分子。初步药理结果显示，其具有良好的抑制ABL和选择性抑制第I类HDAC的活性。本项目将在此设计思路的基础上，结合理性药物设计和计算机辅助药物设计方法，设计结构新颖的目标分子，并在虚拟筛选及初步类药性评价的基础上进行化学合成，同时，分别从细胞和分子水平上评价目标化合物对ABL，HDAC1和肿瘤细胞增殖活性的影响，并进行构效关系研究，从而进一步优化结构。为最终获得具有自主知识产权的抗肿瘤候选药物打下坚实的基础。

中文关键词： BCR/ABL；组蛋白去乙酰化酶；双靶点抑制剂；合成；抗肿瘤

英文摘要： Protein kinase BCR/ABL inhibitor is an hot research topic in the development of antitumor drugs all over the world. Although its theraputic effect is excellent, there are still some problems, such as side effect, drug resistance, etc. Many researches have demonstrated that BCR/ABL inhibitors and HDAC inhibitors have synergistic antitumot effect. Therefore, it is hopeful to develop novel antitumor drugs which target both BCR/ABL and HDAC. Base on our previous work, considering the structure characteristics of these two targets' inhibitors, this project aims to develop molecules with two targets through the principle of molecular integration function. Preliminary pharmacological results showed that these compounds could effectively inhibit ABL and selectively inhibit class I HDAC. Based on this design idea, this project will design novel target compounds though rational drug design and computer aided drug design methods and synthetic work will be carried out after visual screening and preliminary evaluation of drug-likeness. Meanwhile, the inhibitory effect of these compounds on ABL, HDAC1 and the proliferaton of tumor cells will be carried out at cell and molecular levels. The structure activity relationship will be investigated to further modity the chemical structures. We will lay sodid foundaton for the develo

英文关键词： BCR/ABL；HDAC；dual target inhibiors；synthesis；antitumor