Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design

被引：83

作者：

Zhao, Yanlong ^{[1
]}

Zhang, Xi ^{[2
]}

Chen, Yingyi ^{[1
]}

Lu, Shaoyong ^{[1
]}

Peng, Yuefeng ^{[3
]}

Wang, Xiang ^{[2
]}

Guo, Chengliang ^{[2
]}

Zhou, Aiwu ^{[1
]}

Zhang, Jingmiao ^{[1
]}

Luo, Yu ^{[1
]}

Shen, QianCheng ^{[1
]}

Ding, Jian ^{[2
]}

Meng, Linghua ^{[2
]}

Zhang, Jian ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis, Chinese Minist Educ, Dept Pathophysiol,Sch Med, Shanghai 200025, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China

[3] Chinese Acad Sci, Shenzhen Inst Adv Technol, Inst Biomed & Biotechnol, Shenzhen 518055, Guangdong, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 02期

基金：

中国国家自然科学基金;

关键词：

PI3K; PI103; crystal structure; drug design; cancer therapy; BLOCKADE;

D O I：

10.1021/ml400378e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3K alpha-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R-1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3K alpha-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3K alpha inhibitors.

引用

页码：138 / 142

页数：5

共 16 条

[1] Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis [J].