title: A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy.
abstract: Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 μM) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH-11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 μM SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation.
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.|Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.|Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Rania S
authors.initials: RS
authors.lastname: Sulaiman
authors.affiliation: School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Merrigan
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.
authors.forename: Judith
authors.initials: J
authors.lastname: Quigley
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.affiliation: College of Pharmacy, Gachon University, Incheon 406-840, South Korea.
authors.forename: Bit
authors.initials: B
authors.lastname: Lee
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.affiliation: School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Breandán
authors.initials: B
authors.lastname: Kennedy
authors.affiliation: College of Pharmacy, Gachon University, Incheon 406-840, South Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Seo
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.|Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States of America.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Corson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001681:Biological Assay; D002829:Choroid / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D020256:Choroidal Neovascularization / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002867:Chromones / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D058449:Intravitreal Injections; D007814:Larva / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012160:Retina / Q000187:drug effects / Q000473:pathology; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D057134:Antibodies, Neutralizing; D002867:Chromones; D004338:Drug Combinations; C000622107:SH-11037; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D010649:Phenylalanine