Discovery of a Novel Series of Thienopyrimidine as Highly Potent and Selective PI3K Inhibitors

被引：42

作者：

Han, Fangbin ^{[1
]}

Lin, Songwen ^{[1
]}

Liu, Peng ^{[1
]}

Liu, Xiujie ^{[1
]}

Tao, Jing ^{[1
]}

Deng, Xiaobing ^{[1
]}

Yi, Chongqin ^{[1
]}

Xu, Heng ^{[1
]}

机构：

[1] PKUCare Pharmaceut R&D Ctr, Biotech Innovat Works, Beijing 102206, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 04期

基金：

中国博士后科学基金;

关键词：

thienopyrimidines; phosphoinositide; 3-kinase; mammalian target of rapamycin; dual inhibitors; selective PI3K inhibitors; DUAL INHIBITORS; HUMAN CANCER; PATHWAY; TARGET; DERIVATIVES; RAPAMYCIN; KINASE; MTOR; IDENTIFICATION; GROWTH;

D O I：

10.1021/ml5005014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway provides a promising new approach for cancer therapy. Through a rational design, a novel series of thienopyrimidine was discovered as highly potent and selective PI3K inhibitors. These thienopyrimidine derivatives were demonstrated to bear nanomolar PI3K alpha inhibitory potency with over 100-fold selectivity against mTOR kinase. The lead compounds 6g and 6k showed good developability profiles in cell-based proliferation and ADME assays. In this communication, their design, synthesis, structure activity relationship, selectivity, and some developability properties are described.

引用

页码：434 / 438

页数：5

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