THR-687, a potent small molecule integrin antagonist, holds promise as a therapeutic approach for back-of-the-eye vascular pathologies

Purpose Pathologic neovascularization and vessel leakage are key drivers for vision loss in several back-of-the-eye diseases, such as diabetic retinopathy and age-related macular degeneration. In the eye, integrin receptors play an important role in (pathological) angiogenesis and vascular leakage. Blocking integrin receptors has the potential to inhibit these processes, independent of anti-VEGF responsiveness. In this study, we evaluated the integrin-blocking and anti-angiogenic properties of THR-687, a novel small molecule integrin antagonist. Methods Competition ELISA assays were used to assess the ability of THR-687 to compete with the binding of integrin receptors to their natural ligands. The inhibitory effect of THR-687 on the migration of human umbilical vein endothelial cells (HUVECs) was evaluated in the ORIS cell migration assay. The effect of THR-687 on blood vessel outgrowth was evaluated in an ex vivo mouse choroidal explant model. Cytotoxicity of THR-687 on human retinal microvascular endothelial cells (HRMVECs) was evaluated using the CellTox Green assay. The safety profile of THR-687 was further evaluated using hERG and genotoxicity assays. Results THR-687 was found to inhibit multiple integrin receptors belonging to the RGD class with IC50 values in the low nanomolar range, including, but not limited to, αvβ3, αvβ5 and α5β1. THR-687 potently inhibited the migration of HUVECs in the ORIS system (IC50 of 82 ± 11 nM). Ex vivo choroidal vessel sprouting was dose-dependently inhibited by THR-687 (IC50 of 1.50 ± 0.27 μM). No relevant cytotoxicity signal was observed on HRMVECs at concentrations ranging from 0.25 nM to 20 μM, and in vitro pharmacological profiling studies indicated a good safety profile. Conclusions THR-687 is a potent drug candidate for the treatment of diabetic eye disease.