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

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

doi:10.1126/sciadv.aaz7815

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

Sci Adv. 2020 Jul 29;6(31):eaaz7815. doi: 10.1126/sciadv.aaz7815. eCollection 2020 Jul.

Authors

Yue Li¹, Ahmad M N Alhendi¹, Mei-Chun Yeh¹, Mina Elahy¹, Fernando S Santiago¹, Nandan P Deshpande², Ben Wu¹, Enoch Chan¹, Shafqat Inam¹, Leonel Prado-Lourenco¹, Jessica Marchand³, Rohan D Joyce³, Lorna E Wilkinson-White⁴, Mark J Raftery⁵, Meidong Zhu^{6

7

8}, Samuel J Adamson⁸, François Barnat⁹, Karen Viaud-Quentric⁹, Jim Sockler¹⁰, Joel P Mackay¹¹, Andrew Chang^{7

8

12}, Paul Mitchell¹³, Sebastian M Marcuccio^{3

14}, Levon M Khachigian¹

Affiliations

¹ Vascular Biology and Translational Research, School of Medical Sciences and UNSW Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
² Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
³ Advanced Molecular Technologies Pty Ltd, Scoresby, VIC 3179, Australia.
⁴ Sydney Analytical Core Facility, University of Sydney, NSW 2006, Australia.
⁵ Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW 2052, Australia.
⁶ New South Wales Tissue Bank, New South Wales Organ and Tissue Donation Service, South Eastern Sydney Local Health District, Kogarah, NSW 2217, Australia.
⁷ Save Sight Institute, Discipline of Clinical Ophthalmology and Eye Health, University of Sydney, NSW 2006, Australia.
⁸ GreenLight Clinical Pty. Ltd., Woolloomooloo, NSW 2011, Australia.
⁹ Iris Pharma, La Gaude 06610, France.
¹⁰ Statistical Operations and Programming, Datapharm Australia Pty. Ltd., Drummoyne, NSW 2047, Australia.
¹¹ School of Life and Environmental Sciences, University of Sydney, NSW 2006, Australia.
¹² Sydney Eye Hospital, Sydney NSW 2000 and University of Sydney, NSW 2006, Australia.
¹³ Centre for Vision Research, Department of Ophthalmology, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Westmead, NSW 2145, Australia.
¹⁴ La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.

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-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.

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / pharmacology
Animals
Capillary Permeability*
Humans
Mice
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / genetics
Proto-Oncogene Proteins c-fos / metabolism
Rabbits
Rats
Vascular Cell Adhesion Molecule-1* / metabolism
Vascular Cell Adhesion Molecule-1* / pharmacology
Vascular Endothelial Growth Factor A / metabolism

Substances

Angiogenesis Inhibitors
FOSB protein, human
Fosb protein, mouse
Fosb protein, rat
Proto-Oncogene Proteins c-fos
Vascular Cell Adhesion Molecule-1
Vascular Endothelial Growth Factor A