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Beschreibung

A pyrrolyl benzoic acid that effectively competes against ephrin-B3 for EphA4 binding as well as against ephrin-A1/-A2/-A3/-A5 for EphA2 and EphA4 binding by targeting EphA2/A4 high affinity ephrin-binding pocket in a reversible manner (Ki = 6-10 and 11-14 µ,M against ephrin-A5 binding to EphA4 and EphA2, respectively), exhibiting much reduced or no potency against ephrin-A4 for EphA2/EphA4 binding, ephrin-A5 for EphA3/A5/A6/A7 binding, ephrin-B2 for B1/B2/B3/B4/B6 binding, or ephrin-B2 for EphA4 binding. Shown to inhibit 0.1 µ,g/mL ephrin-A1-Fc fusion-induced EphA2 phosphorylation in COS7 (by 92% at 200 µ,M) and 0.5 µ,g/mL ephrin-A5-Fc fusion-induced EphA4 phosphorylation in HT22 neuronal cultures (by 42% and 79% respectively, at 300 and 400 µ,M) without any cytotoxicity (up to 400 µ,M and 3 days in HT22 cultures). Also effective toward chicken and zebrafish EphA4 orthologs as evidenced by its efficacy in preventing 1 µ,g/mL ephrin-A5-Fc-induced growth cone collapse of neurons in 6-d chicken embryo retina (by 100% at 400 µ,M) ex vivo and in fully rescuing human mutant SOD-1 A4V transgene-induced axonopathy in zebrafish embryos (500 µ,M, treatment period from 6 to 30 hpf) in vivo., A pyrrolyl benzoic acid that effectively competes against ephrin-B3 for EphA4 binding as well as against ephrin-A1/-A2/-A3/-A5 for EphA2 and EphA4 binding by targeting EphA2/A4 high affinity ephrin-binding pocket in a reversible manner, exhibiting much reduced or no potency against ephrin-A4 for EphA2/EphA4 binding, ephrin-A5 for EphA3/A5/A6/A7 binding, ephrin-B2 for B1/B2/B3/B4/B6 binding, or ephrin-B2 for EphA4 binding. Shown to inhibit ephrin-A1-induced EphA2 phosphorylation (by 92% at 200 µ,M) and ephrin-A5-induced EphA4 phosphorylation (by 79% at 400 µ,M) in cultures in vitro and prevent ephrin-A5-induced growth cone collapse of neurons in 6-d chicken embryo retina (by 100% at 400 µ,M) ex vivo, as well as rescue human mutant SOD-1 A4V transgene-induced axonopathy in zebrafish embryos (500 µ,M from 6 to 30 hpf) in vivo.