Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors

doi:10.1038/aps.2011.23

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

	Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors
	Tong, Lin-jiang 1,2; Xie, Hua2 ; Peng, Ting 2; Liu, Xiao-feng 3; Xin, Xian-liang 2; Huang, Xun2 ; Chen, Si-meng 2; Liu, Hong-yan 2; Li, Hong-lin 3; Geng, Mei-yu2
刊名	ACTA PHARMACOLOGICA SINICA
	2011-07
卷号	32 期号:7 页码:930-938
关键词	insulin like growth factor 1 receptor (IGF1R) anticancer drug enzyme-linked immunosorbent assay (ELISA) hematoxylin cell proliferation apoptosis HL-60 cell line
ISSN号	1671-4083
DOI	10.1038/aps.2011.23
文献子类	Article
英文摘要	Aim: The insulin-like growth factor-1 receptor (IGF1R) is over-expressed in a wide variety of tumors and contributes to tumor cell proliferation, metastasis and drug resistance. The aim of this study was to establish a sensitive screening platform to identify novel IGF1R inhibitors. Methods: The catalytic domain of IGF1R was expressed using the Bac-to-Bac baculovirus expression system. The screening platform for IGF1R inhibitors was established based on ELISA. The binding profile of IGF1R with the inhibitors was predicted with molecular docking and then subjected to the surface plasmon resonance (SPR) approach. The growth inhibition of cancer cells by the inhibitors was assessed with MTT assay. Apoptosis was analyzed using flow cytometry and Western blotting. Results: A naturally occurring small molecule compound hematoxylin was identified as the most potent inhibitor (IC50 value=1.8 +/- 0.1 mu mol/L) within a library of more than 200 compounds tested. Molecular simulation predicted the possible binding mode of hematoxylin with IGF1R. An SPR assay further confirmed that hematoxylin bound directly to IGF1R with high binding affinity (Kd=4.2x10(-6) mol/L). In HL-60 cancer cells, hematoxylin inactivated the phosphorylation of IGF1R and downstream signaling and therefore suppressed cell proliferation. Mechanistic studies revealed that hematoxylin induced apoptosis in HL-60 cells via both extrinsic and intrinsic pathways. Conclusion: A simple, sensitive ELISA-based screening platform for identifying IGF1R inhibitors was established. Hematoxylin was identified as a promising IGF1R inhibitor with effective antitumor activity that deserves further investigation.
资助项目	Key New Drug Creation and Manufacturing Program[2009ZX09103-001] ; Key New Drug Creation and Manufacturing Program[2009ZX09103-102] ; Shanghai Science and Technology Committee[10431902600] ; Shanghai Key Lab of Chemical Biology[SKLCB-2008-03]
WOS关键词	STAGE BREAST-CANCER ; KINASE INHIBITORS ; TYROSINE KINASE ; APOPTOSIS ; IGF-1R ; VITRO ; CARCINOMA ; PATHWAYS ; IMATINIB ; ANALOGS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4251703
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000292447600009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278485]
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	Yin, Ming
作者单位	1.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.E China Univ, Sch Pharm, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China
推荐引用方式 GB/T 7714	Tong, Lin-jiang,Xie, Hua,Peng, Ting,et al. Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2011,32(7):930-938.
APA	Tong, Lin-jiang.,Xie, Hua.,Peng, Ting.,Liu, Xiao-feng.,Xin, Xian-liang.,...&Ding, Jian.(2011).Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors.ACTA PHARMACOLOGICA SINICA,32(7),930-938.
MLA	Tong, Lin-jiang,et al."Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors".ACTA PHARMACOLOGICA SINICA 32.7(2011):930-938.