Crystal Structures of PI3K alpha Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design
文献类型：期刊论文
| 作者 | Zhao, Yanlong2; Zhang, Xi1; Chen, Yingyi2; Lu, Shaoyong2; Peng, Yuefeng3; Wang, Xiang1; Guo, Chengliang1; Zhou, Aiwu2; Zhang, Jingmiao2; Luo, Yu2 |
| 刊名 | ACS MEDICINAL CHEMISTRY LETTERS
 |
| 出版日期 | 2014-02 |
| 卷号 | 5期号:2页码:138-142 |
| 关键词 | PI3K PI103 crystal structure drug design cancer therapy |
| ISSN号 | 1948-5875 |
| DOI | 10.1021/ml400378e |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | BLOCKADE ; GLIOMA |
| 资助项目 | Program for New Century Excellent Talents in University[NCET-12-0355] ; Shanghai Rising-Star Program[13QA1402300] ; National Science & Technology Major Project[2012ZX09301-001] ; National Natural Science Foundation of China[81322046] ; National Natural Science Foundation of China[81302698] ; National Natural Science Foundation of China[81021062] ; National Natural Science Foundation of China[21002062] ; National Natural Science Foundation of China[21102090] ; Knowledge Innovation Program of Chinese Academy of Sciences[KSCX2-EW-Q-3] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000331493600008 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277201]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Meng, Linghua |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 2.Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis, Chinese Minist Educ, Dept Pathophysiol,Sch Med, Shanghai 200025, Peoples R China; 3.Chinese Acad Sci, Shenzhen Inst Adv Technol, Inst Biomed & Biotechnol, Shenzhen 518055, Guangdong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Yanlong,Zhang, Xi,Chen, Yingyi,et al. Crystal Structures of PI3K alpha Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design[J]. ACS MEDICINAL CHEMISTRY LETTERS,2014,5(2):138-142. |
| APA | Zhao, Yanlong.,Zhang, Xi.,Chen, Yingyi.,Lu, Shaoyong.,Peng, Yuefeng.,...&Zhang, Jian.(2014).Crystal Structures of PI3K alpha Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.ACS MEDICINAL CHEMISTRY LETTERS,5(2),138-142. |
| MLA | Zhao, Yanlong,et al."Crystal Structures of PI3K alpha Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design".ACS MEDICINAL CHEMISTRY LETTERS 5.2(2014):138-142. |
入库方式： OAI收割
来源：上海药物研究所
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