VEGF, a vascular endothelial growth factor, stimulates blood vessel formation. It activates endothelial cells (ECs), and induces ECs proliferation and migration. However, VEGF promotes pathological angiogenesis and vasculogenesis to cause disease. Moreover, VEGF overexpression disrupts the balance between angiogenic stimulants and angiogenic inhibitors. In particular, it causes neovascularization in the retina of the eye, and even irreversible blindness occurs. So it is important in eye vascular diseases. And VEGF is highly concentrated in the serum of patients with vascular development diseases. Therefore, the intervention of VEGF activity is of great significance in inhibiting pathological neovascularization. Here we will introduce a multi-target tyrosine kinase inhibitor, DCZ19931, against angiogenesis.
DCZ19931 potently inhibits neovascularization via ERK1/2-MAPK and p38-MAPK singling pathways.
DCZ19931 (1 nM-10 μM; 24 h) targets multiple kinases, without obvious cytotoxicity against human umbilical vein endothelial cells (HUVECs). It (500 nM; 24 h) inhibits (10 ng/mL; 12 h) VEGFs induced proliferation, migration, and tubular formation ability of ECs. It also (500 nM; 24 h) inhibits vascular permeability by down-regulating ICAM-1 expression. In addition, it (500 nM; 24 h) reduces the protein levels of p-ERK1/2, p-p38, and p-JNK in HUVECs.
As for in vivo property, DCZ19931 (2 μL, 1 μg/μL; intravitreal injection; 7 d) shows safety without tissue toxicity in C57BL/6J mice. However, it has anti-angiogenic effects in mouse models. Specifically, it (1 μL, 1 μg/μL; intravitreal injection; single dose) inhibits ocular neovascularization in the oxygen-induced retinopathy (OIR) model. Meanwhile, it (same as above) inhibits ocular neovascularization in the laser-induced choroidal neovascularization (CNV) model.
In summary, DCZ19931 is an ocular neovascularization inhibitor. And it acts function by inhibiting ERK1/2-MAPK and p38-MAPK signals. DCZ19931 significantly inhibits ECs proliferation and migration. It exerts an anti-angiogenic effect in vitro and in vivo.