Novel Combretastatin A4 analogs for Treatment of Retinal Neovascularization

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a common complication of diabetes mellitus and a leading cause of blindness in developed countries. Abnormal angiogenesis in the retina or retinal neovascularization (NV) is one of the major pathological changes in DR. Retinal NV can ultimately result in severe vitreous cavity hemorrhage and/or retinal detachment, leading to severe loss of vision. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of retinal NV. Targeting VEGF receptor (VEGFR) or disruption of VEGF signaling is believed to be a most promising strategy for the pharmacological therapy of ocular NV. Therefore, searching for and developing new drugs to block retinal NV via targeting VEGF signaling or VEGFR have initiated a major research effort with potential of producing novel, potent, efficacious, and marketable drugs for the treatment of DR. Combretastatin A4 (CA4) is a natural tubulin-binding molecule, which has received special attention in the last few years. Combretastatin A4 phosphate (CA4P), a water-soluble prodrug of CA4, has both anti-proliferative and anti-angiogenic activities. CA4P also showed potential inhibition of retinal NV. However, high doses of CA4P caused significant toxicities. Four phase I clinical trials in humans demonstrated the side effects and dose-limiting toxicities of CA4P. Thus, new CA4 analogs with improved anti-angiogenc activities and less side effects are desired. A collaborator of this project has synthesized a series of novel CA4 analogs using SU5416 (a VEGFR signaling inhibitor) as a template. Among 25 novel compounds studied, two promising CA4 analogs displayed more potent anti-tumor activities than CA4 and SU5416. We hypothesize that the novel CA4 analogs have therapeutic potential in the treatment of retinal NV. Our objective is to develop more potent, selective anti-angiogenic drugs, which can prevent and arrest retinal NV. The Phase I project will determine the efficacy of these novel compounds on angiogenesis. Our in vitro studies will evaluate whether these new compounds have anti-angiogenic activity. We will also determine the effect of these novel compounds on retinal NV in oxygen-induced retinopathy (OIR) rat model, which is a commonly used model of proliferative diabetic retinopathy. These studies may identify novel compounds with therapeutic potential for the treatment of retinal NV. This proof-of-concept study will allow future Phase II project to study their toxicities and pharmacokinetics. Therefore, this project, if funded, has potential to generate marketable products for the treatment of a major blinding disease. As retinal NV affects a large population, and as there is no effective drug available on the market, these new anti-angiogenic drugs should have great commercial potential. Retinal neovascularization is a major pathological change leading to vision loss in diabetic retinopathy, which is a leading cause of blindness in the world. Our goal is to develop novel anti-angiogenic drugs for the treatment of retina neovascularization. In this project, we will study the effects of two novel CA4 analogs selected from 25 new compounds on retinal angiogenesis in vitro and in vivo. This proof-of-concept study represents the first step in developing new anti-angiogenic drugs using these CA4 analogs.