title: YLT192, a novel, orally active bioavailable inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy in preclinical models.
abstract: Antagonizing 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.
authors.affiliation: 1] State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China [2].
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: 1] State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China [2].
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Song
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Deliang
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Tinghong
authors.initials: T
authors.lastname: Ye
authors.affiliation: Department of Pathophysiology, School of Basic Medicine, AnHui Medical University, Hefei, 230032, China.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Meng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Guobo
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Senyi
authors.initials: S
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Youli
authors.initials: Y
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
authors.forename: Luoting
authors.initials: L
authors.lastname: Yu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015027:Zebrafish / Q000254:growth & development
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001549:Benzamides; D010848:Picolinic Acids; D042461:Vascular Endothelial Growth Factor A; C000602658:YLT192; D040301:Vascular Endothelial Growth Factor Receptor-2
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