Journal Article

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

Meng-yuan LI Yong-cong LV Lin-jiang TONG Ting PENG Rong QU Tao ZHANG Yi-ming SUN Yi CHEN Li-xin WEI Mei-yu GENG Wen-hu DUAN Hua XIE Jian DING

2016

Overview

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-l-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 pmol/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 IC5o values ranging from 2.2 pmol/L （for U87-MG human glioblastoma cells） to 22.2 pmol/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.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-l-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, pc） for two weeks. Results： Among a panel of 21 kinases tested, DW10075 selectively inhibited VEGFR-1, VEGFR-2 and VEGFR-3 （the ICso 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 pmol/L. DW10075 significantly blocked VEGF-induced activation of VEGFR and its downstream signaling transduction in primary human umbilica 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 IC5o values ranging from 2.2 pmol/L （for U87-MG human glioblastoma cells） to 22.2 pmol/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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Angiogenesis Inhibitors - chemistry / Angiogenesis Inhibitors - therapeutic use / Animals / Biomedical and Life Sciences / Biomedicine / Cell Line, Tumor / Cell Movement - drug effects / Cell Proliferation - drug effects / Chickens / Glioblastoma - blood supply / Glioblastoma - drug therapy / Glioblastoma - metabolism / Glioblastoma - pathology / Human Umbilical Vein Endothelial Cells / Humans / Immunology / Internal Medicine / Male / Medical Microbiology / Mice / Mice, Inbred BALB C / Mice, Nude / Neoplasms - blood supply / Neoplasms - drug therapy / Neoplasms - metabolism / Neoplasms - pathology / Original / original-article / Pharmacology/Toxicology / Pyrimidines - chemistry / Pyrimidines - therapeutic use / Rats, Sprague-Dawley / Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors / Receptors, Vascular Endothelial Growth Factor - metabolism / Vaccine / 体外 / 信号转导通路 / 内皮细胞增殖 / 小分子 / 抗肿瘤活性 / 血管内皮生长因子受体 / 选择性抑制剂 / 酶联免疫吸附法