Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR

doi:10.1016/j.bcp.2012.01.019

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	Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR
	Chen, Si-meng 1; Liu, Jia-li 1; Wang, Xiang 1; Liang, Chris 2; Ding, Jian1 ; Meng, Ling-hua1
刊名	BIOCHEMICAL PHARMACOLOGY
	2012-05-01
卷号	83 期号:9 页码:1183-1194
关键词	X-387 mTOR kinase Cancer therapy Cell migration Autophagy
ISSN号	0006-2952
DOI	10.1016/j.bcp.2012.01.019
文献子类	Article
英文摘要	The mammalian target of rapamycin (mTOR), is deregulated in about 50% of human malignancies and exists in two complexes: mTORC1 and mTORC2. Rapalogs partially inhibit mTORC1 through allosteric binding to mTORC1 and their efficacy is modest as a cancer therapy. A few mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2 have been reported to possess potent anticancer activities. Herein, we designed and synthesized a series of pyrazolopyrimidine derivatives targeting mTOR kinase domain and X-387 was identified as a promising lead. X-387 selectively inhibited mTOR in an ATP-competitive manner while sparing a panel of kinases from the PIKK family. X-387 blocked mTORC1 and mTORC2-mediacted signaling pathway in cell lines with activated mTOR signaling and in rapamycin-resistant cells. Specifically, X-387 inhibited phosphorylation of Ala at T308, which is thought to be a target of PDK1 but not mTOR. Such activity was not due to inhibition of PI3K since X-387 did not inhibit translocation of AKT to the cell membrane. X-387 induced autophagy as observed for other mTOR inhibitors, while induced autophagy is pro-survival since concurrent inhibition of autophagy by 3-MA reinforced the antiproliferative activity of mTOR inhibitors. X-387 also inhibited cell motility, which is associated with decrease in activity of small GTPases such as RhoA, Rac1 and Cdc42. Taken together, X-387 is a promising compound lead targeting mTOR and with a wide spectrum anticancer activity among tumor cell lines. The data also underscores the complexity of the mTOR signaling pathways which are far from being understood. (C) 2012 Elsevier Inc. All rights reserved.
资助项目	National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301-001] ; National Natural Science Foundation of China[81021062] ; National Natural Science Foundation of China[81173079] ; Chinese Academy of Sciences[KSCX2-EW-Q-3] ; SA-SIBS[00000000]
WOS关键词	MAMMALIAN TARGET ; BINDING PARTNER ; ADVANCED NSCLC ; RAPAMYCIN ; AUTOPHAGY ; AKT ; CYTOSKELETON ; KINASE ; CANCER ; RAPTOR
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000301906900006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278106]
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	Ding, Jian
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.Xcovery LLC, W Palm Beach, FL USA
推荐引用方式 GB/T 7714	Chen, Si-meng,Liu, Jia-li,Wang, Xiang,et al. Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR[J]. BIOCHEMICAL PHARMACOLOGY,2012,83(9):1183-1194.
APA	Chen, Si-meng,Liu, Jia-li,Wang, Xiang,Liang, Chris,Ding, Jian,&Meng, Ling-hua.(2012).Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR.BIOCHEMICAL PHARMACOLOGY,83(9),1183-1194.
MLA	Chen, Si-meng,et al."Inhibition of tumor cell growth, proliferation and migration by X-387, a novel active-site inhibitor of mTOR".BIOCHEMICAL PHARMACOLOGY 83.9(2012):1183-1194.