Phenotype-Based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis

<p>Retinal angiogenesis is tightly regulated to meet oxygenation and nutritional requirements. In diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, uncontrolled angiogenesis can lead to blindness. Our goal is to better understand the molecular processes controlling retinal angiogenesis and discover novel drugs that inhibit retinal neovascularization. Phenotype-based chemical screens were performed using the ChemBridge Diverset<sup style="margin: 0px; padding: 0px; border: 0px; outline-style: none; font-size: 0.85em; font-family: 'Lucida Sans Unicode', Arial, 'Lucida Grande', Tahoma, Verdana, Helvetica, sans-serif; line-height: 0; text-align: justify; color: rgb(64, 56, 56);">TM</sup> library and inhibition of hyaloid vessel angiogenesis in Tg(<em style="margin: 0px; padding: 0px; border: 0px; outline-style: none; font-size: 12.8px; font-family: 'Lucida Sans Unicode', Arial, 'Lucida Grande', Tahoma, Verdana, Helvetica, sans-serif; line-height: 19.2px; text-align: justify; vertical-align: baseline; color: rgb(64, 56, 56);">fli1:EGFP</em>) zebrafish. 2-[(<em style="margin: 0px; padding: 0px; border: 0px; outline-style: none; font-size: 12.8px; font-family: 'Lucida Sans Unicode', Arial, 'Lucida Grande', Tahoma, Verdana, Helvetica, sans-serif; line-height: 19.2px; text-align: justify; vertical-align: baseline; color: rgb(64, 56, 56);">E</em>)-2-(Quinolin-2-yl)vinyl]phenol, (quininib) robustly inhibits developmental angiogenesis at 4–10 μM in zebrafish and significantly inhibits angiogenic tubule formation in HMEC-1 cells, angiogenic sprouting in aortic ring explants, and retinal revascularization in oxygen-induced retinopathy mice. Quininib is well tolerated in zebrafish, human cell lines, and murine eyes. Profiling screens of 153 angiogenic and inflammatory targets revealed that quininib does not directly target VEGF receptors but antagonizes cysteinyl leukotriene receptors 1 and 2 (CysLT<sub style="margin: 0px; padding: 0px; border: 0px; outline-style: none; font-size: 0.85em; font-family: 'Lucida Sans Unicode', Arial, 'Lucida Grande', Tahoma, Verdana, Helvetica, sans-serif; line-height: 0; text-align: justify; color: rgb(64, 56, 56);">1–2</sub>) at micromolar IC<sub style="margin: 0px; padding: 0px; border: 0px; outline-style: none; font-size: 0.85em; font-family: 'Lucida Sans Unicode', Arial, 'Lucida Grande', Tahoma, Verdana, Helvetica, sans-serif; line-height: 0; text-align: justify; color: rgb(64, 56, 56);">50</sub> values. In summary, quininib is a novel anti-angiogenic small-molecule CysLT receptor antagonist. Quininib inhibits angiogenesis in a range of cell and tissue systems, revealing novel physiological roles for CysLT signaling. Quininib has potential as a novel therapeutic agent to treat ocular neovascular pathologies and may complement current anti-VEGF biological agents.</p>