Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB-VCAM-1 axis
Vascular 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 dibenzoxazep...
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| creator | Li, Yue Alhendi, Ahmad M N Yeh, Mei-Chun Elahy, Mina Santiago, Fernando S Deshpande, Nandan P Wu, Ben Chan, Enoch Inam, Shafqat Prado-Lourenco, Leonel Marchand, Jessica Joyce, Rohan D Wilkinson-White, Lorna E Raftery, Mark J Zhu, Meidong Adamson, Samuel J Barnat, François Viaud-Quentric, Karen Sockler, Jim Mackay, Joel P Chang, Andrew Mitchell, Paul Marcuccio, Sebastian M Khachigian, Levon M |
| description | Vascular 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-A
administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A
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. |
| doi_str_mv | 10.1126/sciadv.aaz7815 |
| format | Article |
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administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A
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.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.aaz7815</identifier><identifier>PMID: 32923607</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Angiogenesis Inhibitors - pharmacology ; Animals ; Capillary Permeability ; Health and Medicine ; Humans ; Mice ; Molecular Biology ; Neovascularization, Pathologic - drug therapy ; Neovascularization, Pathologic - genetics ; Proto-Oncogene Proteins c-fos - metabolism ; Rabbits ; Rats ; SciAdv r-articles ; Vascular Cell Adhesion Molecule-1 - metabolism ; Vascular Cell Adhesion Molecule-1 - pharmacology ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Science advances, 2020-07, Vol.6 (31), p.eaaz7815</ispartof><rights>Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).</rights><rights>Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2020 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-91bcfc6dc9613975801cca7c9f110afae9f0cc48c561917225f168e35f4e24493</citedby><cites>FETCH-LOGICAL-c390t-91bcfc6dc9613975801cca7c9f110afae9f0cc48c561917225f168e35f4e24493</cites><orcidid>0000-0003-1213-3428 ; 0000-0002-9397-0895 ; 0000-0001-8530-2814 ; 0000-0002-0324-8728 ; 0000-0002-5304-9188 ; 0000-0002-6584-2562 ; 0000-0001-7508-8033 ; 0000-0003-3446-0323</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450479/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450479/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32923607$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Yue</creatorcontrib><creatorcontrib>Alhendi, Ahmad M N</creatorcontrib><creatorcontrib>Yeh, Mei-Chun</creatorcontrib><creatorcontrib>Elahy, Mina</creatorcontrib><creatorcontrib>Santiago, Fernando S</creatorcontrib><creatorcontrib>Deshpande, Nandan P</creatorcontrib><creatorcontrib>Wu, Ben</creatorcontrib><creatorcontrib>Chan, Enoch</creatorcontrib><creatorcontrib>Inam, Shafqat</creatorcontrib><creatorcontrib>Prado-Lourenco, Leonel</creatorcontrib><creatorcontrib>Marchand, Jessica</creatorcontrib><creatorcontrib>Joyce, Rohan D</creatorcontrib><creatorcontrib>Wilkinson-White, Lorna E</creatorcontrib><creatorcontrib>Raftery, Mark J</creatorcontrib><creatorcontrib>Zhu, Meidong</creatorcontrib><creatorcontrib>Adamson, Samuel J</creatorcontrib><creatorcontrib>Barnat, François</creatorcontrib><creatorcontrib>Viaud-Quentric, Karen</creatorcontrib><creatorcontrib>Sockler, Jim</creatorcontrib><creatorcontrib>Mackay, Joel P</creatorcontrib><creatorcontrib>Chang, Andrew</creatorcontrib><creatorcontrib>Mitchell, Paul</creatorcontrib><creatorcontrib>Marcuccio, Sebastian M</creatorcontrib><creatorcontrib>Khachigian, Levon M</creatorcontrib><title>Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB-VCAM-1 axis</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Vascular 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-A
administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A
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. 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Alhendi, Ahmad M N ; Yeh, Mei-Chun ; Elahy, Mina ; Santiago, Fernando S ; Deshpande, Nandan P ; Wu, Ben ; Chan, Enoch ; Inam, Shafqat ; Prado-Lourenco, Leonel ; Marchand, Jessica ; Joyce, Rohan D ; Wilkinson-White, Lorna E ; Raftery, Mark J ; Zhu, Meidong ; Adamson, Samuel J ; Barnat, François ; Viaud-Quentric, Karen ; Sockler, Jim ; Mackay, Joel P ; Chang, Andrew ; Mitchell, Paul ; Marcuccio, Sebastian M ; Khachigian, Levon M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-91bcfc6dc9613975801cca7c9f110afae9f0cc48c561917225f168e35f4e24493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Angiogenesis Inhibitors - pharmacology</topic><topic>Animals</topic><topic>Capillary Permeability</topic><topic>Health and Medicine</topic><topic>Humans</topic><topic>Mice</topic><topic>Molecular Biology</topic><topic>Neovascularization, Pathologic - drug therapy</topic><topic>Neovascularization, Pathologic - genetics</topic><topic>Proto-Oncogene Proteins c-fos - metabolism</topic><topic>Rabbits</topic><topic>Rats</topic><topic>SciAdv r-articles</topic><topic>Vascular Cell Adhesion Molecule-1 - metabolism</topic><topic>Vascular Cell Adhesion Molecule-1 - pharmacology</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Yue</creatorcontrib><creatorcontrib>Alhendi, Ahmad M N</creatorcontrib><creatorcontrib>Yeh, Mei-Chun</creatorcontrib><creatorcontrib>Elahy, Mina</creatorcontrib><creatorcontrib>Santiago, Fernando S</creatorcontrib><creatorcontrib>Deshpande, Nandan P</creatorcontrib><creatorcontrib>Wu, Ben</creatorcontrib><creatorcontrib>Chan, Enoch</creatorcontrib><creatorcontrib>Inam, Shafqat</creatorcontrib><creatorcontrib>Prado-Lourenco, Leonel</creatorcontrib><creatorcontrib>Marchand, Jessica</creatorcontrib><creatorcontrib>Joyce, Rohan D</creatorcontrib><creatorcontrib>Wilkinson-White, Lorna E</creatorcontrib><creatorcontrib>Raftery, Mark J</creatorcontrib><creatorcontrib>Zhu, Meidong</creatorcontrib><creatorcontrib>Adamson, Samuel J</creatorcontrib><creatorcontrib>Barnat, François</creatorcontrib><creatorcontrib>Viaud-Quentric, Karen</creatorcontrib><creatorcontrib>Sockler, Jim</creatorcontrib><creatorcontrib>Mackay, Joel P</creatorcontrib><creatorcontrib>Chang, Andrew</creatorcontrib><creatorcontrib>Mitchell, Paul</creatorcontrib><creatorcontrib>Marcuccio, Sebastian M</creatorcontrib><creatorcontrib>Khachigian, Levon M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Yue</au><au>Alhendi, Ahmad M N</au><au>Yeh, Mei-Chun</au><au>Elahy, Mina</au><au>Santiago, Fernando S</au><au>Deshpande, Nandan P</au><au>Wu, Ben</au><au>Chan, Enoch</au><au>Inam, Shafqat</au><au>Prado-Lourenco, Leonel</au><au>Marchand, Jessica</au><au>Joyce, Rohan D</au><au>Wilkinson-White, Lorna E</au><au>Raftery, Mark J</au><au>Zhu, Meidong</au><au>Adamson, Samuel J</au><au>Barnat, François</au><au>Viaud-Quentric, Karen</au><au>Sockler, Jim</au><au>Mackay, Joel P</au><au>Chang, Andrew</au><au>Mitchell, Paul</au><au>Marcuccio, Sebastian M</au><au>Khachigian, Levon M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB-VCAM-1 axis</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2020-07-01</date><risdate>2020</risdate><volume>6</volume><issue>31</issue><spage>eaaz7815</spage><pages>eaaz7815-</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Vascular 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-A
administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A
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.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>32923607</pmid><doi>10.1126/sciadv.aaz7815</doi><orcidid>https://orcid.org/0000-0003-1213-3428</orcidid><orcidid>https://orcid.org/0000-0002-9397-0895</orcidid><orcidid>https://orcid.org/0000-0001-8530-2814</orcidid><orcidid>https://orcid.org/0000-0002-0324-8728</orcidid><orcidid>https://orcid.org/0000-0002-5304-9188</orcidid><orcidid>https://orcid.org/0000-0002-6584-2562</orcidid><orcidid>https://orcid.org/0000-0001-7508-8033</orcidid><orcidid>https://orcid.org/0000-0003-3446-0323</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Angiogenesis Inhibitors - pharmacology Animals Capillary Permeability Health and Medicine Humans Mice Molecular Biology Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - genetics Proto-Oncogene Proteins c-fos - metabolism Rabbits Rats SciAdv r-articles Vascular Cell Adhesion Molecule-1 - metabolism Vascular Cell Adhesion Molecule-1 - pharmacology Vascular Endothelial Growth Factor A - metabolism |
| title | Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB-VCAM-1 axis |
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