以PI4KIIα为靶点抗肿瘤抑制剂的筛选及优化

项目名称： 以PI4KIIα为靶点抗肿瘤抑制剂的筛选及优化

项目编号： No.81472839

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李江美

作者单位： 中国科学院生物物理研究所

项目金额： 78万元

中文摘要： 本课题组前期工作表明PI4KIIα是一个潜在的乳腺癌治疗靶点（Oncogen,2010;Cell death and disease, under review）。但是截至目前仍未有PI4KIIα特异抑制剂报道。为解决这一问题我们解析了PI4KIIα的晶体结构（Nature Communications，2014）,并结合虚拟药物设计和本课题组自主完善的高通量PI4KIIα酶活筛选技术，得到了2个抑制效率较好的PI4KIIα抑制剂。基于此本项目将通过蛋白小分子复合体结构指导虚拟药物设计的方法提高小分子抑制效率；酶谱分析，转录组学调控比对及小分子抑制效果对PI4KIIα依赖性来确定其特异性；通过免疫缺陷鼠肿瘤异源移植模型（多种细胞系及PDX模型）来确定其抗肿瘤效果；通过水溶性改进，纳米载体包装提高其的生物利用度，降低其生物毒性;最终筛选到PI4KIIα特异高效的抗肿瘤抑制剂。

中文关键词： 肿瘤治疗；PI4KIIα；靶向治疗；抑制剂筛选；抑制剂优化

英文摘要： We have previously reported that PI4KIIαis a new tumor regulator （Oncogene,2010）, and suppressed PI4KIIα expression can enhanced the anti-tumor effect of EGFR targeted therapy (Cell death and disease, under review). All above suggested that PI4KIIα could be an potential breast cancer target. However, there is no PI4KIIα specific inhibitors available still now. Recently, we solved the crystal structure of PI4KIIα ( Nature Communications， 2014）, and then initially screened the ATP competitive inhibitors of PI4KIIα by using virtual screening and high-throug enzyme activity screening methods which were optimized by our own group. We have got 2 potential PI4KIIα specific inhibitors now. In this project, we will first confirm and optimize the existing PI4KIIα inhibitors. In order to improve the efficiency of the inhibitors, the crystal structure of PI4KIIα complexed with its inhibitors will be solved to identify the interaction site, and then optimizing virtual screening could be taken. The kinase panel analysis, comparing the difference of transcriptomics between PI4KIIα inhibitors treatment and PI4KIIα knock down cells, shRNA method combined with cellular PI4P detection assay will be used to confirm the specific of the inhibitors. Furthermore, we will use tumor xenograft model (including patient-derivedxenograft （PDX） model) to confirm the anti-tumor effect of selected inhibitors. Finally, we will enhance the bioavailability and reduce the toxicity by drug chemistry modifying and enclosed the inhibitors into nanocarriers. The final goal is getting a low toxicity and high effect PI4KIIα targeted anti-tumor inhibitors.

英文关键词： cancer therapy;PI4KIIα;targeted therapy;inhibitors screening;inhibitors optimizing