Crystal Structures of PI3K alpha Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design

doi:10.1021/ml400378e

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Crystal Structures of PI3K alpha Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design
	Zhao, Yanlong 2; Zhang, Xi 1; Chen, Yingyi 2; Lu, Shaoyong 2; Peng, Yuefeng 3; Wang, Xiang 1; Guo, Chengliang 1; Zhou, Aiwu 2; Zhang, Jingmiao 2; Luo, Yu 2
刊名	ACS MEDICINAL CHEMISTRY LETTERS
	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.
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关键词	BLOCKADE ; GLIOMA
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000331493600008
内容类型	期刊论文
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.