Three Nitrogen Atoms Turn Old Kinase Inhibitors Into New Targetable Remedy

Pathological neovascularization in the eye is a significant contributor to vision loss in diseases such as age-related macular degeneration and diabetic retinopathy. While anti-VEGF biologics are effective, they require repeated intravitreal injections. Here, we report a novel principle for designing photoactivatable VEGFR2 inhibitors, along with two examples, EYE1090 and EYE1118. Azido-functionalization in these molecules enables light-triggered receptor binding while preserving potent inhibition in the dark. Both compounds exhibit significantly enhanced activity upon exposure to green light that reaches the human retina, also in the elderly. In vitro, the compounds robustly inhibited angiogenesis and endothelial migration that was further potentiated by light. In vivo, orally administered EYE1090 and EYE1118 suppressed VEGF-induced retinal leakage in rats and reduced lesion size in a mouse model of choroidal neovascularization, but did not show acute hepatotoxicity. Our findings introduce a novel light-targeted pharmacological approach exploiting the natural light focusing anatomy of the eye.