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

Autor: Li Y; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Alhendi AMN; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Yeh MC; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Elahy M; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Santiago FS; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Deshpande NP; Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia., Wu B; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Chan E; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Inam S; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Prado-Lourenco L; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia., Marchand J; Advanced Molecular Technologies Pty Ltd, Scoresby, VIC 3179, Australia., Joyce RD; Advanced Molecular Technologies Pty Ltd, Scoresby, VIC 3179, Australia., Wilkinson-White LE; Sydney Analytical Core Facility, University of Sydney, NSW 2006, Australia., Raftery MJ; Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW 2052, Australia., Zhu M; New South Wales Tissue Bank, New South Wales Organ and Tissue Donation Service, South Eastern Sydney Local Health District, Kogarah, NSW 2217, Australia.; Save Sight Institute, Discipline of Clinical Ophthalmology and Eye Health, University of Sydney, NSW 2006, Australia.; GreenLight Clinical Pty. Ltd., Woolloomooloo, NSW 2011, Australia., Adamson SJ; GreenLight Clinical Pty. Ltd., Woolloomooloo, NSW 2011, Australia., Barnat F; Iris Pharma, La Gaude 06610, France., Viaud-Quentric K; Iris Pharma, La Gaude 06610, France., Sockler J; Statistical Operations and Programming, Datapharm Australia Pty. Ltd., Drummoyne, NSW 2047, Australia., Mackay JP; School of Life and Environmental Sciences, University of Sydney, NSW 2006, Australia., Chang A; Save Sight Institute, Discipline of Clinical Ophthalmology and Eye Health, University of Sydney, NSW 2006, Australia.; GreenLight Clinical Pty. Ltd., Woolloomooloo, NSW 2011, Australia.; Sydney Eye Hospital, Sydney NSW 2000 and University of Sydney, NSW 2006, Australia., Mitchell P; Centre for Vision Research, Department of Ophthalmology, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Westmead, NSW 2145, Australia., Marcuccio SM; Advanced Molecular Technologies Pty Ltd, Scoresby, VIC 3179, Australia.; La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia., Khachigian LM; Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2020 Jul 29; Vol. 6 (31), pp. eaaz7815. Date of Electronic Publication: 2020 Jul 29 (Print Publication: 2020).
DOI: 10.1126/sciadv.aaz7815
Abstrakt: 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 165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A 165 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.
(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).)
Databáze: MEDLINE
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