DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo

doi:10.1038/aps.2015.117

	DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo
	Li, Meng-yuan 1,2,3; Lv, Yong-cong 4; Tong, Lin-jiang 3; Peng, Ting 3; Qu, Rong 1,3; Zhang, Tao 1,5; Sun, Yi-ming 3; Chen, Yi3 ; Wei, Li-xin 1,2; Geng, Mei-yu3
刊名	ACTA PHARMACOLOGICA SINICA
	2016-03
卷号	37 期号:3 页码:398-407
关键词	DW10075 VEGF/VEGF receptor inhibitor antitumor angiogenesis U87-MG human glioblastoma
ISSN号	1671-4083
DOI	10.1038/aps.2015.117
文献子类	Article
英文摘要	Aim: Targeting the VEGF/VEGF receptor (VEGFR) pathway has proved to be an effective antiangiogenic approach for cancer treatment. Here, we identified 6-((2-((3-acetamidophenyl)amino)pyrimidin-4-yl)oxy)-N-phenyl-1-naphthamide (designated herein as DW10075) as a novel and highly selective inhibitor of VEGFRs. Methods: In vitro tyrosine kinase activity was measured using ELISA, and intracellular signaling pathway proteins were detected by Western blot analysis. Endothelial cell proliferation was examined with CCK-8 assays, and tumor cell proliferation was determined with SRB assays. Cell migration, tube formation and rat aortic ring assays were used to detect antiangiogenic activity. Antitumor efficacy was further evaluated in U87-MG human glioblastoma xenograft tumors in nude mice receiving DW10075 (500 mg.kg(-1).d(-1), po) for two weeks. Results: Among a panel of 21 kinases tested, DW10075 selectively inhibited VEGFR-1, VEGFR-2 and VEGFR-3 (the IC50 values were 6.4, 0.69 and 5.5 nmol/L, respectively), but did not affect 18 other kinases including FGFR and PDGFR at 10 mu mol/L. DW10075 significantly blocked VEGF-induced activation of VEGFR and its downstream signaling transduction in primary human umbilical vein endothelial cells (HUVECs), thus inhibited VEGF-induced HUVEC proliferation. DW10075 (1-100 nmol/L) dose-dependently inhibited VEGF-induced HUVEC migration and tube formation and suppressed angiogenesis in both the rat aortic ring model and the chicken chorioallantoic membrane model. Furthermore, DW10075 exhibited anti-proliferative activity against 22 different human cancer cell lines with IC50 values ranging from 2.2 mu mol/L (for U87-MG human glioblastoma cells) to 22.2 mu mol/L (for A375 melanoma cells). In U87-MG xenograft tumors in nude mice, oral administration of DW10075 significantly suppressed tumor growth, and reduced the expression of CD31 and Ki67 in the tumor tissues. Conclusion: DW10075 is a potent and highly selective inhibitor of VEGFR that deserves further development.
资助项目	National Natural Science Foundation of China[81173080] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[81374063] ; National Key Technology R&D Program of the Ministry of Science and Technology of China[2012BAI27B02] ; Research Program of Qinghai province[2012-T-Y23]
WOS关键词	METASTATIC COLORECTAL-CANCER ; RENAL-CELL CARCINOMA ; ANGIOGENESIS INHIBITORS ; BEVACIZUMAB ; AXITINIB ; TARGETS ; KINASES ; POTENT
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5652525
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000371426900012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276125]
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	Duan, Wen-hu; Xie, Hua; Ding, Jian
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 2.Chinese Acad Sci, Northwest Inst Plateau Biol, Pharmacol & Safety Evaluat Key Lab Tibetan Med Qi, Xining 810008, Peoples R China; 3.Chinese Acad Sci, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China; 5.Shanghai Tech Univ, Shanghai 200120, Peoples R China
推荐引用方式 GB/T 7714	Li, Meng-yuan,Lv, Yong-cong,Tong, Lin-jiang,et al. DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo[J]. ACTA PHARMACOLOGICA SINICA,2016,37(3):398-407.
APA	Li, Meng-yuan.,Lv, Yong-cong.,Tong, Lin-jiang.,Peng, Ting.,Qu, Rong.,...&Ding, Jian.(2016).DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo.ACTA PHARMACOLOGICA SINICA,37(3),398-407.
MLA	Li, Meng-yuan,et al."DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo".ACTA PHARMACOLOGICA SINICA 37.3(2016):398-407.