DCZ19931, a novel multi-targeting kinase inhibitor, inhibits ocular neovascularization

Abstract

Neovascularization is a prominent cause of irreversible blindness in a variety of ocular diseases. Current therapies for pathological neovascularization are concentrated on the suppression of vascular endothelial growth factors (VEGF). Despite the remarkable efficacy of anti-VEGF drugs, several problems still exist, including ocular complications and drug resistance. Thus, it is still required to design novel drugs for anti-angiogenic treatment. This study aimed to investigate the anti-angiogenic effects of a small molecule multi-target tyrosine kinase inhibitor, DCZ19931, on ocular neovascularization. The results showed that administration of DCZ19931 at the tested concentrations did not cause obvious cytotoxicity and tissue toxicity. DCZ19931 could reduce the size of choroidal neovascularization (CNV) lesions in laser-induced CNV model and suppress ocular neovascularization in oxygen-induced retinopathy (OIR) model. DCZ19931 could suppress VEGF-induced proliferation, migration, and tube formation ability of endothelial cells, exhibiting similar anti-angiogenic effects as Ranibizumab. DCZ19931 could reduce the levels of intercellular cell adhesion molecule-1 (ICAM-1) expression in vivo and in vitro. Network pharmacology prediction and western blots revealed that DCZ19931 exerted its anti-angiogenic effects through the inactivation of ERK1/2-MAPK signaling and p38-MAPK signaling. In conclusion, this study indicates that DCZ19931 is a promising drug for anti-angiogenic therapy for ocular diseases.

Proteomic study of vitreous in proliferative diabetic retinopathy patients after treatment with aflibercept: a quantitative analysis based on 4D label-free technique

“…Anti-VEGF drugs may affect these underlying pathophysiological processes differently, and more studies on drug-specific phenotypic changes after drug use in PDR patients are necessary. VEGF in PDR controls angiogenesis through the VEGFR1 and VEGFR2 signal pathways [10] , the latter being the main receptor for VEGF-induced neoangiogenesis and permeability-enhancing effects [11] . The aflibercept selected in this experiment is a chimeric receptor consisting of VEGF receptor 1 (VEGFR1) and VEGFR2 binding domains, which binds with high affinity to VEGF-A, VEGF-B, and placental growth factor.…”