TY - JOUR T1 - Novel small molecule JP-153 targets the Src-FAK-paxillin signaling complex to inhibit VEGF-induced retinal angiogenesis JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.116.105031 SP - mol.116.105031 AU - Jordan J Toutounchian AU - Jayaprakash Pagadala AU - Duane D Miller AU - Jerome Baudry AU - Frank Park AU - Edward Chaum AU - Charles R Yates Y1 - 2016/01/01 UR - http://molpharm.aspetjournals.org/content/early/2016/11/09/mol.116.105031.abstract N2 - Targeting vascular endothelial growth factor, VEGF, is a common treatment strategy for neovascular eye disease, a major cause of vision loss in diabetic retinopathy and age-related macular degeneration. However, the decline in clinical efficacy over time in many patients suggests that monotherapy of anti-VEGF protein therapeutics may benefit from adjunctive treatments. Our previous work has shown that through decreased activation of the cytoskeletal protein paxillin, growth factor-induced ischemic retinopathy in the murine OIR model could be inhibited. In this study, we demonstrated that VEGF-dependent activation of the Src/FAK/paxillin signalsome is required for human retinal endothelial cell migration and proliferation. Specifically, the disruption of focal adhesion kinase (FAK) and paxillin interactions, using the small molecule JP-153, inhibited Src-dependent phosphorylation of paxillin (Y118) and downstream activation of Akt (S473) resulting in reduced migration and proliferation of RECs stimulated with VEGF. However, this effect did not prevent the initial activation of either Src or FAK. Furthermore, topical application of a JP-153-loaded microemulsion affected the hallmark features of pathologic retinal angiogenesis, reducing neovascular tuft formation and increased avascular area, in a dose-dependent manner. In conclusion, our results suggest that using small molecules to modulate the FA protein paxillin is an effective strategy to treat pathological retinal neovascularization. To our knowledge, this is the first paradigm validating modulation of paxillin to inhibit angiogenesis. As such, we have identified and developed a novel class of small molecules aimed at targeting FA protein interactions which are essential for pathological neovascularization in the eye. ER -