DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo
文献类型：期刊论文
| 作者 | Li, Meng-yuan1,2,3; Lv, Yong-cong4; Tong, Lin-jiang3; Peng, Ting3; Qu, Rong1,3; Zhang, Tao1,5; Sun, Yi-ming3; Chen, Yi3 ; Wei, Li-xin1,2; Geng, Mei-yu3
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 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. |
| WOS关键词 | METASTATIC COLORECTAL-CANCER ; RENAL-CELL CARCINOMA ; ANGIOGENESIS INHIBITORS ; BEVACIZUMAB ; AXITINIB ; TARGETS ; KINASES ; POTENT |
| 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研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5652525 |
| WOS记录号 | WOS:000371426900012 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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