title: HL-217, a new topical anti-angiogenic agent, inhibits retinal vascular leakage and pathogenic subretinal neovascularization in Vldlr⁻/⁻ mice.
abstract: HL-217 is a new synthetic angiogenesis inhibitor. Platelet derived growth factor (PDGF) is a vasoactive factor and has been implicated in proliferative retinopathies. In this study, we examined the mechanism of action and efficacy of topical application of HL-217 on subretinal neovascularization in very low-density lipoprotein receptor knockout (Vldlr(-/-)) mice. In three-week-old male Vldlr(-/-) mice, HL-217 (1.5 or 3mg/ml) was administered twice per day for 4 weeks by topical eye drop instillation. Neovascular areas were then measured. We used a protein array to evaluate the expression levels of angiogenic factors. The inhibitory effect of HL-217 on the PDGF-BB/PDGFRβ interaction was evaluated in vitro. The neovascular area in the Vldlr(-/-) mice was significantly reduced by HL-217. Additionally, HL-217 decreased the expression levels of PDGF-BB protein and VEGF mRNA. Moreover, HL-217 dose-dependently inhibited the PDGF-BB/PDGFRβ interaction (IC50=38.9 ± 0.7 μM). These results suggest that HL-217 is a potent inhibitor of PDGF-BB. HL-217, when applied topically, is an effective inhibitor of subretinal neovascularization due to its ability to inhibit the pro-angiogenic effects of PDGF-BB.
authors.affiliation: Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.
authors.forename: Junghyun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.
authors.forename: Chan-Sik
authors.initials: CS
authors.lastname: Kim
authors.affiliation: Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.
authors.forename: Kyuhyung
authors.initials: K
authors.lastname: Jo
authors.affiliation: Research and Development Center, Hanlim Pharm. Co. Ltd., 1656-10, Seocho-dong, Seocho-gu, Seoul, South Korea.
authors.forename: Yun-Seok
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Research and Development Center, Hanlim Pharm. Co. Ltd., 1656-10, Seocho-dong, Seocho-gu, Seoul, South Korea.
authors.forename: Hyun-Gyu
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Research and Development Center, Hanlim Pharm. Co. Ltd., 1656-10, Seocho-dong, Seocho-gu, Seoul, South Korea.
authors.forename: Geun-Hyeog
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.
authors.forename: Yun Mi
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.
authors.forename: Eunjin
authors.initials: E
authors.lastname: Sohn
authors.affiliation: Korean Medicine Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea. Electronic address: jskim@kiom.re.kr.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000077214:Becaplermin; D001578:Benzopyrans / Q000494:pharmacology*; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D037102:Lectins / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D012160:Retina / Q000187:drug effects*; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000235:genetics; D015398:Signal Transduction
chemical_list: C000595877:6-amino-4-(N-(4-chlorophenyl)-N-(1H-imidazol-2ylmethyl)amino)-3-hydroxyl-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran; D020533:Angiogenesis Inhibitors; D001578:Benzopyrans; D007093:Imidazoles; D037102:Lectins; D008024:Ligands; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D011973:Receptors, LDL; C036053:VLDL receptor; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta; D016650:Fluorescein-5-isothiocyanate
keywords: HL-217; Platelet derived growth factor; Subretinal neovascularization