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

Yue Li | Zendy; Ahmad M. N. Alhendi | Zendy; Mei-Chun Yeh | Zendy; Mina Elahy | Zendy; Fernando S. Santiago | Zendy; Nandan Deshpande | Zendy; Ben J. Wu | Zendy; Enoch Chan | Zendy; Shafqat Inam | Zendy; Leonel Prado-Lourenço | Zendy; Jessica Marchand | Zendy; Rohan D. Joyce | Zendy; Lorna WilkinsonWhite | Zendy; Mark J. Raftery | Zendy; Meidong Zhu | Zendy; Samuel Adamson | Zendy; François Barnat | Zendy; Karen Viaud-Quentric | Zendy; Jim Sockler | Zendy; Joel P. Mackay | Zendy; Andrew Chang | Zendy; Paul Mitchell | Zendy; Sebastian M. Marcuccio | Zendy; Levon M. Khachigian | Zendy

Open Access

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

Author(s) -

Yue Li,

Ahmad M. N. Alhendi,

Mei-Chun Yeh,

Mina Elahy,

Fernando S. Santiago,

Nandan Deshpande,

Ben J. Wu,

Enoch Chan,

Shafqat Inam,

Leonel Prado-Lourenço,

Jessica Marchand,

Rohan D. Joyce,

Lorna WilkinsonWhite,

Mark J. Raftery,

Meidong Zhu,

Samuel Adamson,

François Barnat,

Karen Viaud-Quentric,

Jim Sockler,

Joel P. Mackay,

Andrew Chang,

Paul Mitchell,

Sebastian M. Marcuccio,

Levon M. Khachigian

Publication year - 2020

Publication title -

science advances

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.928

H-Index - 146

ISSN - 2375-2548

DOI - 10.1126/sciadv.aaz7815

Subject(s) - fosb , angiogenesis , vcam 1 , vascular permeability , permeability (electromagnetism) , chemistry , microbiology and biotechnology , cancer research , biology , biochemistry , cell adhesion molecule , endocrinology , icam 1 , transcription factor , gene , membrane

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.

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