基于嘧啶与三嗪母核的PI3Kα/mTOR双靶点抑制剂的设计、合成及生物活性研究

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.

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。

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，已成为近年来抗肿瘤药物研究的热点。PF-05212384是辉瑞公司研发的PI3K/mTOR双靶点抑制剂，目前处于临床II期，主要存在分子量大、亚型选择性不高且需注射给药等不足。基于此，本项目以PF-05212384为先导，以提高亚型选择性、改善类药性并提高抑瘤效果为目标进行了衍生物的设计和合成。经过多轮衍生物设计，共合成了五个系列56个目标化合物，并对所合成衍生物进行了PI3Kα/mTOR双靶点及部分化合物的PI3Ks亚型选择性测试，发现多个激酶抑制活性及亚型选择性优于阳性对照PF-05212384的化合物。通过对多种肿瘤细胞株的抗增殖活性测试，发现所合成化合物对肿瘤细胞株具有较强的抑制活性，尤其是在HCT116细胞上，表现出显著优于阳性对照的抗增殖活性。Western blotting实验证实所合成化合物为强效PI3K/mTOR双靶点抑制剂。人工胃肠液及肝微粒体稳定性实验结果显示，所设计合成的衍生物具有优于阳性对照的体外稳定性。深入的体内药动学、药效学及抗肿瘤机制研究还在开展中。.该项目的实施，筛选出了抗肿瘤活性与类药性俱佳的pan-PI3K/mTOR抑制剂PT-12、选择性PI3Kδ/mTOR双靶点抑制剂PT-41及选择性mTOR抑制剂PT-63，为后续基于PI3K/Akt/mTOR信号通路的抗肿瘤药物研发提供了新结构。整个项目的完成共发表SCI论文8篇，中文核心期刊论文6篇，已申请中国发明专利2项。