PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KII alpha, Inhibits the Growth of Breast Cancer Cells

doi:10.1158/0008-5472.CAN-17-0484

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	PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KII alpha, Inhibits the Growth of Breast Cancer Cells
	Li, Jiangmei 2,3; Gao, Zhen 2,4; Zhao, Dan 4,5; Zhang, Lunfeng 2,4; Qiao, Xinhua 2,4; Zhao, Yingying 2,3; Ding, Hong5 ; Zhang, Panpan 3,4,6; Lu, Junyan 5; Liu, Jia3
刊名	CANCER RESEARCH
	2017-11-15
卷号	77 期号:22 页码:6253-6266
ISSN号	0008-5472
DOI	10.1158/0008-5472.CAN-17-0484
文献子类	Article
英文摘要	While phosphatidylinositol 4-kinase (PI4KII alpha) has been identified as a potential target for antitumor therapy, the clinical applications of PI4KII alpha are limited by a lack of specific inhibitors. Here we report the first small-molecule inhibitor (SMI) of human PI4KII alpha. Docking-based and ligand-based virtual screening strategies were first employed to identify promising hits, followed by two rounds of kinase activity inhibition validation. 2-(3-(4-Chlorobenzoyl) thioureido)-4-ethyl-5-methylthiophene-3-carboxamide (PI-273) exhibited the greatest inhibitory effect on PI4KII alpha kinase activity (IC50 = 0.47 mmol/L) and suppressed cell proliferation. Surface plasmon resonance and thermal shift assays indicated that PI-273 interacted directly with PI4KII alpha. Kinetic analysis identified PI-273 as a reversible competitive inhibitor with respect to the substrate phosphatidylinositol (PI), which contrasted with most other PI kinase inhibitors that bind the ATP binding site. PI-273 reduced PI4P content, cell viability, and AKT signaling in wild typeMCF-7 cells, but not in PI4KII alpha knockout MCF-7 cells, indicating that PI-273 is highly selective for PI4KII alpha. Mutant analysis revealed a role of palmitoylation insertion in the selectivity of PI-273 for PI4KII alpha. In addition, PI-273 treatment retarded cell proliferation by blocking cells in G(2)-M, inducing cell apoptosis and suppressing colony-forming ability. Importantly, PI-273 significantly inhibited MCF-7 cell-induced breast tumor growth without toxicity. PI-273 is the first substrate-competitive, subtype-specific inhibitor of PI4KII alpha, the use of which will facilitate evaluations of PI4KII alpha as a cancer therapeutic target. (C) 2017 AACR.
资助项目	National Key R&D Program of China[2017YFA0504000] ; National Key R&D Program of China[2016YFC0903100] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development[00000000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020316] ; National Natural Sciences Foundation of China[31570857] ; National Natural Sciences Foundation of China[31225012] ; National Natural Sciences Foundation of China[31101021] ; National Natural Sciences Foundation of China[81472839] ; National Natural Sciences Foundation of China[81430084] ; National Natural Sciences Foundation of China[81625022] ; National Natural Sciences Foundation of China[21472208] ; "863" National High-Technology Development Program of China[0A200202D03] ; National Key Scientific Instrument & Equipment Development Program of China[2012YQ03026010] ; Beijing Natural Science Foundation[7132156] ; Science and Technology Commission of Shanghai Municipality[15431903100] ; [NNCAS-2012-2]
WOS关键词	II PHOSPHATIDYLINOSITOL 4-KINASE ; ISOFORM-SELECTIVE INHIBITION ; THERMAL SHIFT ASSAY ; ALZHEIMERS-DISEASE ; GENETIC ALGORITHM ; KEY COMPONENT ; KINASE ; DISCOVERY ; RECEPTOR ; DOCKING
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000415107900019
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272402]
专题	药物发现与设计中心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	Luo, Cheng; Chen, Chang
作者单位	1.Acad Mil Med Sci, State Key Lab Toxicol & Med Counter Measures, Beijing, Peoples R China; 2.Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing, Peoples R China; 3.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China; 4.Univ Chinese Acad Sci, Beijing, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 6.Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China; 7.Beijing Inst Brain Disorders, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Li, Jiangmei,Gao, Zhen,Zhao, Dan,et al. PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KII alpha, Inhibits the Growth of Breast Cancer Cells[J]. CANCER RESEARCH,2017,77(22):6253-6266.
APA	Li, Jiangmei.,Gao, Zhen.,Zhao, Dan.,Zhang, Lunfeng.,Qiao, Xinhua.,...&Chen, Chang.(2017).PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KII alpha, Inhibits the Growth of Breast Cancer Cells.CANCER RESEARCH,77(22),6253-6266.
MLA	Li, Jiangmei,et al."PI-273, a Substrate-Competitive, Specific Small-Molecule Inhibitor of PI4KII alpha, Inhibits the Growth of Breast Cancer Cells".CANCER RESEARCH 77.22(2017):6253-6266.