YLT192, a Novel, Orally Active Bioavailable Inhibitor of VEGFR2 Signaling with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models

• DOI: 10.1038/srep06031
• Publication Date: 2014-08-12T09:04:59Z
• Authors: Yong Xia; Xuejiao Song; Deliang Li; Tinghong Ye; Youzhi Xu; Hongjun Lin; Nana Meng; Guobo Li; Senyi Deng; Shuang Zhang; Li Liu; Yongxia Zhu; Jun Zeng; Qian Lei; Youli Pan; Yuquan Wei; Yinglan Zhao; Luoting Yu
• Keywords: Male; Mice, Inbred BALB C; 0303 health sciences; Binding Sites; Embryo, Nonmammalian; Mice, Nude; Neovascularization, Physiologic; Angiogenesis Inhibitors; Antineoplastic Agents; HCT116 Cells; Article; 3. Good health; Mice; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Neoplasms; Benzamides; Human Umbilical Vein Endothelial Cells; Animals; Humans; Female; Picolinic Acids; Cell Proliferation

AbstractAntagonizing vascular endothelial growth factor receptor 2 (VEGFR2) to block angiogenesis has been applied toward cancer therapy for its role in promoting cancer growth and metastasis. However, most these clinical anticancer drugs have unexpected side effects. Development of novel VEGFR2 inhibitors with less toxicity remains an urgent need. In this study, we describe a novel, well-tolerated and orally active VEGFR2 inhibitor, YLT192, which inhibits tumor angiogenesis and growth. YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVEC. Zebrafish embryonic models and alginate-encapsulated tumor cell assays indicated YLT192 also inhibited angiogenesis in vivo. Moreover, YLT192 could directly inhibit proliferation and induce apoptosis of cancer cells in vitro and in vivo. Oral administration of YLT192 at a dose of 100 mg/kg/day could markedly inhibited human tumor xenograft growth without causing obvious toxicities. It decreased microvessel densities (MVD) in tumor sections. It also shows good safety profiles in the studies with mice and rats. Taken together, these preclinical evaluations suggest that YLT192 inhibits angiogenesis and may be a promising anticancer drug candidate.