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Article: Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis

TitleThermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis
Authors
Issue Date2020
PublisherAmerican Association for the Advancement of Science: Science Advances. The Journal's web site is located at http://www.scienceadvances.org/
Citation
Science Advances, 2020, v. 6 n. 31, article no. eaaz7815 How to Cite?
AbstractVascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months’ storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.
Persistent Identifierhttp://hdl.handle.net/10722/295534
ISSN
2020 Impact Factor: 14.136
2020 SCImago Journal Rankings: 5.928
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, Y-
dc.contributor.authorAlhendi, AMN-
dc.contributor.authorYeh, MC-
dc.contributor.authorElahy, M-
dc.contributor.authorSantiago, FS-
dc.contributor.authorDeshpande, NP-
dc.contributor.authorWu, B-
dc.contributor.authorChan, E-
dc.contributor.authorInam, S-
dc.contributor.authorPrado-Lourenco, L-
dc.contributor.authorMarchand, J-
dc.contributor.authorJoyce, RD-
dc.contributor.authorWilkinson-White, LE-
dc.contributor.authorRaftery, MJ-
dc.contributor.authorZhu, M-
dc.contributor.authorAdamson, SJ-
dc.contributor.authorBarnat, F-
dc.contributor.authorViaud-Quentric, K-
dc.contributor.authorSockler, J-
dc.contributor.authorMackay, JP-
dc.contributor.authorChang, A-
dc.contributor.authorMitchell, P-
dc.contributor.authorMarcuccio, SM-
dc.contributor.authorKhachigian, LM-
dc.date.accessioned2021-01-25T11:16:14Z-
dc.date.available2021-01-25T11:16:14Z-
dc.date.issued2020-
dc.identifier.citationScience Advances, 2020, v. 6 n. 31, article no. eaaz7815-
dc.identifier.issn2375-2548-
dc.identifier.urihttp://hdl.handle.net/10722/295534-
dc.description.abstractVascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months’ storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science: Science Advances. The Journal's web site is located at http://www.scienceadvances.org/-
dc.relation.ispartofScience Advances-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleThermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis-
dc.typeArticle-
dc.identifier.emailChan, E: enocha@hku.hk-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1126/sciadv.aaz7815-
dc.identifier.pmid32923607-
dc.identifier.pmcidPMC7450479-
dc.identifier.scopuseid_2-s2.0-85090873217-
dc.identifier.hkuros320940-
dc.identifier.volume6-
dc.identifier.issue31-
dc.identifier.spagearticle no. eaaz7815-
dc.identifier.epagearticle no. eaaz7815-
dc.identifier.isiWOS:000556543100008-
dc.publisher.placeUnited States-

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