PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo

doi:10.1007/s10549-010-1302-4

	PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo
	Ma, Jin-gui 1; Huang, He 2; Chen, Si-meng 1; Chen, Yi1 ; Xin, Xian-liang 1; Lin, Li-ping 1; Ding, Jian1 ; Liu, Hong2 ; Meng, Ling-hua1
刊名	BREAST CANCER RESEARCH AND TREATMENT
	2011-11
卷号	130 期号:1 页码:85-96
关键词	PH006 Src kinase Breast cancer Anti-metastasis
ISSN号	0167-6806
DOI	10.1007/s10549-010-1302-4
文献子类	Article
英文摘要	The central role of Src in tumor progression and metastasis has validated it as an attractive therapeutic target for the treatment of human breast cancer. The aim of this study was to identify potential Src kinase inhibitor, explore its activity, and mechanism of action in human breast cancer. A strategy integrating focused combinatorial library design, virtual screening, chemical synthesis, and high-throughput screening was adopted and a novel 6-hydrazinopurine-based inhibitor of c-Src kinase PH006 was obtained. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay. The binding mode between PH006 and Src was profiled by surface plasmon resonance approach and molecular simulation. The anti-proliferative activity was evaluated by Sulforhodamin B (SRB) and Colony formation. The anti-invasion and anti-migration activities were assessed by trans-well and wound healing assay. Results indicated that PH006 was an ATP-competitive Src inhibitor, which selectively inhibited c-Src with an IC50 of 0.38 mu M among a panel of 14 diverse tyrosine kinases. PH006 potently inhibited c-Src phosphorylation and c-Src-dependent signal transduction, resulting in inhibition of cell proliferation, migration, and invasion in human breast cancer MDA-MB-231 cells. Further study demonstrated that the anti-proliferative activity of PH006 was ascribed to its capability to arrest cells in G1 phase, while its anti-motility activity was related to suppression of MMP2/9 and HGF secretion. Moreover, PH006 exhibited potent activity against tumor growth as well as metastasis of human breast cancer MDA-MB-435 xenograft beard in nude mice, which was accompanied with reduced Src/FAK signaling in tumor tissue. Taken together, PH006 is a novel selective inhibitor of c-Src and possesses potent activity against breast cancer growth and metastasis, which could be potentially developed as a lead candidate against breast cancers with elevated Src tyrosine kinase activity.
资助项目	National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program''[2009ZX09301-001] ; National Natural Science Foundation of China[30721005] ; National Natural Science Foundation of China[20721003] ; National Natural Science Foundation of China[20872153] ; Science and Technology Commission of Shanghai[07dz05906]
WOS关键词	C-SRC ; TYROSINE KINASE ; CELL-LINES ; HGF TRANSCRIPTION ; CARCINOMA-CELLS ; NUDE-MICE ; INVASION ; ABL ; SKI-606 ; POTENT
WOS研究方向	Oncology
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000295363200009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278362]
专题	药物化学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药理学第一研究室
通讯作者	Meng, Ling-hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Ma, Jin-gui,Huang, He,Chen, Si-meng,et al. PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo[J]. BREAST CANCER RESEARCH AND TREATMENT,2011,130(1):85-96.
APA	Ma, Jin-gui.,Huang, He.,Chen, Si-meng.,Chen, Yi.,Xin, Xian-liang.,...&Meng, Ling-hua.(2011).PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo.BREAST CANCER RESEARCH AND TREATMENT,130(1),85-96.
MLA	Ma, Jin-gui,et al."PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo".BREAST CANCER RESEARCH AND TREATMENT 130.1(2011):85-96.