PI3K-Akt-mTOR通路是调控细胞诸多生理功能的主要信号通路之一，其异常激活与肿瘤的发生与发展密切相关。PI3K/mTOR双靶点抑制剂在增强药效、降低耐药性等方面具有独特优势，已成为近年来小分子靶向抗肿瘤药物研究的热门方向。目前进入临床研究的PI3K/mTOR双靶点抑制候选药物多半存在PI3Ks亚型选择性不高、类药性差等问题。本项目以高活性的PI3K/mTOR双靶点抑制剂5p及候选药物PF-05212384为先导化合物，基于激酶亚型晶体结构的不同，借助于计算机辅助药物设计，以提高化合物的PI3Kα亚型选择性并改善类药特性为目标进行衍生物理性设计、合成、生物活性与类药性评价。通过本项目，力争筛选到活性强、亚型选择性好、安全性高且类药特征优良的PI3Kα/mTOR双靶点抑制剂，建立系统的构效关系，为该类双靶点抑制剂的创新药物研究提供理论参考。

The phosphatidylinostiol-3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) is one of the most important cellular signaling pathways, which plays crucial roles in cell growth, proliferation, survival, apoptosis and is frequently dysregulated in human cancers. Dual PI3K/mTOR inhibitors possess some unique privileges in improving potency and decreasing drug resistance, and thus becoming a hot area for the development of novel small molecular targeted antitumor drugs. Hitherto, several dual PI3K/mTOR inhibitors are being underwent clinical evaluation. Though good therapeutic potentiality they revealed, most of them are pan-PI3K/mTOR inhibitors. A high proportion of human cancers are revealed to rely strongly on P110α for survival and thus, non subtype selective inhibition may cause off-target effects compromising therapeutic utility. Besides, poor drug-like properties, such as large molecular weight and low solubility, are also inherent in them which need to be improved. In this project, we take 5p, a potent dual pyrimidine PI3K/mTOR inhibitor that found in our previous study, and clinical candidate PF-05212384 as lead compounds, diverse series of derivatives will be rationally designed based on the the crystal structures of kinase-inhibitor complex using computer-aided drug design and the target compounds are supposed to possess improving PI3Kα subtype selectivity and drug-like properties. The accomplishment of this project will provide novel dual PI3Kα/mTOR inhibitors with potent kinase inhibitory activities, good subtype selectivity, high safety, desirable drug-like properties and therefore, afford theoretic reference for the development of innovative drugs based on PI3K pathway.