Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors

针对炭疽毒素受体的新型血管生成抑制剂

基本信息

批准号：
8268448
负责人：
MICHAEL SEAN ROGERS
金额：
$ 44.35万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8268448
关键词：
Address Affinity Amino Acids Angiogenesis Inhibitors Anthrax disease Antigens Arthritis Binding Biochemical Biological Assay Biological Process Blindness Blood Vessels Blood capillaries Boston Burn injury Cardiovascular Diseases Cells Choroidal Neovascularization Clinical Trials Collaborations Complex Corneal Neovascularization Data Development Diabetic Retinopathy Disease Emerging Communicable Diseases Endothelial Cells Exhibits Extracellular Matrix Eye diseases FDA approved Fibroblast Growth Factor 2 Fluorescence Resonance Energy Transfer Gene Proteins Generations Glaucoma Goals Growth Growth Factor Health Herpetic Keratitis Human Immunoglobulin Fragments In Vitro Individual Infection Investigation Keratoplasty Laboratories Lasers Lead Ligands Lucentis Macular degeneration Malignant Neoplasms Mediating Modeling Morphogenesis Neovascular Glaucoma Outcome Panzem Pathology Pathway interactions Patients Pharmaceutical Chemistry Pharmacotherapy Process Property Proteins Research Retinopathy of Prematurity Revlimid Role Screening procedure Series Signal Pathway Signal Transduction Signaling Molecule Source Testing Thalidomide Therapeutic Toxic effect Trachoma United States National Institutes of Health Validation Vascular Endothelial Growth Factors Vision Work angiogenesis anthrax protective factor anthrax toxin anthrax toxin receptors antiangiogenesis therapy base bevacizumab biodefense capillary design effective therapy experience high throughput screening improved in vivo inhibitor/antagonist innovation member migration mouse model mutant novel ocular angiogenesis pre-clinical receptor receptor binding skills small molecule tissue culture tumor endothelial marker 8 tumor growth

项目摘要

Angiogenesis dependant disease is a major cause of blindness in the developed world, and there remains a generalized outstanding need for broadly active antiangiogenesis therapies which do not inhibit just a single growth factor. We have discovered that anthrax protective antigen mutants (e.g. PASSSR) can powerfully suppress corneal neovascularization induced by multiple growth factors. Our long-range goal is to understand the mechanism by which this suppression is accomplished and develop appropriate therapeutics based on this mechanism. Our working hypotheses is that binding of endogenous ligand(s) to the anthrax toxin receptors (ANTXR1/TEM8 and/or ANTXR2/CMG2) is important in angiogenic processes, and that inhibition of this interaction by competing ligands will inhibit angiogenesis. We will employ several strategies to test this hypothesis. First, we will explain the biochemical mechanism responsible for the observed antiangiogenic activity of PASSSR. We will definitively identify both the specific receptor(s) that mediate the antiangiogenic effect inhibited by PASSSR and the signaling molecule(s) associated with that effect. Second, we will identify small molecule ATR inhibitors and assess their antiangiogenic properties ex vivo. Relevant small molecule inhibitors will be isolated using high throughput screening assays developed as a part of the NIH Roadmap Initiative. The antiangiogenic activity of the identified molecules will then be evaluated in tissue culture. Third, we will assess the ability of isolated ATR inhibitors to inhibit ocular angiogenesis in vivo. Antiangiogenic activity will be evaluated using two mouse models of ocular angiogenesis: the corneal neovascularization model, and a laser-induced choroidal neovascularization model. Successful completion of these studies will both establish the anthrax toxin receptor(s) as appropriate targets for antiangiogenic therapy and provide small molecule lead compounds for broad spectrum antiangiogenic therapies. Pathologies addressed by successful completion of this proposal would thus encompass disorders of ocular angiogenesis such as macular degeneration, diabetic retinopathy, retinopathy of prematurity, and glaucoma, corneal neovascularization associated with conditions such as Herpetic Keratitis, Trachoma, burns, and revascularization of corneal transplants, and other angiogenesis-dependant diseases such as cancer, arthritis, and cardiovascular disease. Hence, these studies are likely to have a significant impact on human health. We have shown that large protein inhibitors of the anthrax toxin receptors can inhibit corneal neovascularization and other angiogenesis-dependant diseases. We seek to understand the mechanism by which this inhibition occurs and identify small molecules with similar activity. These molecules, or similar molecules can then be used to treat corneal neovascularization, and other angiogenesis-dependant diseases (e.g. macular degeneration, diabetic retinopathy, retinopathy of prematurity, cancer, cardiovascular disease, arthritis, etc.).

血管生成依赖性疾病是发达国家失明的主要原因，并且对于广泛有效的抗血管生成疗法仍然存在普遍的突出需求，这些疗法不仅仅抑制单一生长因子。我们发现炭疽保护性抗原突变体（例如 PASSSR）可以强力抑制多种生长因子诱导的角膜新生血管形成。我们的长期目标是了解实现这种抑制的机制并开发适当的治疗方法基于这个机制。我们的工作假设是内源配体与炭疽病的结合毒素受体（ANTXR1/TEM8 和/或 ANTXR2/CMG2）在血管生成过程中很重要，并且通过竞争性配体抑制这种相互作用将抑制血管生成。我们将采用多种策略检验这个假设。首先，我们将解释造成观察到的现象的生化机制 PASSSR 的抗血管生成活性。我们将最终确定介导 PASSSR 抑制抗血管生成作用以及与该作用相关的信号分子。第二，我们将鉴定小分子 ATR 抑制剂并评估其离体抗血管生成特性。相关小分子抑制剂将使用 NIH 开发的高通量筛选测定法进行分离路线图倡议。然后将在组织中评估所识别分子的抗血管生成活性文化。第三，我们将评估分离的 ATR 抑制剂在体内抑制眼部血管生成的能力。将使用两种眼部血管生成小鼠模型来评估抗血管生成活性：角膜新生血管模型和激光诱导脉络膜新生血管模型。顺利完成这些研究都将确定炭疽毒素受体作为抗血管生成治疗的适当靶点并为广谱抗血管生成疗法提供小分子先导化合物。病理学因此，成功完成该提案所解决的问题将涵盖眼部血管生成疾病如黄斑变性、糖尿病性视网膜病变、早产儿视网膜病变、青光眼、角膜与疱疹性角膜炎、沙眼、烧伤等疾病相关的新生血管形成角膜移植的血运重建以及其他血管生成依赖性疾病，例如癌症、关节炎、和心血管疾病。因此，这些研究可能对人类健康产生重大影响。我们已经证明炭疽毒素受体的大蛋白抑制剂可以抑制角膜新血管形成和其他血管生成依赖性疾病。我们试图通过以下方式了解该机制发生这种抑制并鉴定具有类似活性的小分子。这些分子或类似分子然后分子可用于治疗角膜新生血管和其他血管生成依赖性疾病（例如黄斑变性、糖尿病性视网膜病变、早产儿视网膜病变、癌症、心血管疾病、关节炎等）。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Galloyl Carbohydrates with Antiangiogenic Activity Mediated by Capillary Morphogenesis Gene 2 (CMG2) Protein Binding.

没食子酰碳水化合物具有由毛细血管形态发生基因 2 (CMG2) 蛋白结合介导的抗血管生成活性。

DOI：
10.1021/acs.jmedchem.8b01988
发表时间：
2019
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
G-Doyagüez,Elisa;Carrero,Paula;Madrona,Andrés;Rodriguez-Salamanca,Patricia;Martínez-Gualda,Belén;Camarasa,MaríaJosé;Jimeno,MaríaLuisa;Bennallack,PhilipR;Finnell,JordanG;Tsang,Tsz-Ming;Christensen,KennethA;San-Félix,Ana;Rogers,
通讯作者：
Rogers,

1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2.

DOI：
10.1021/jm301558t
发表时间：
2013-03-14
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Cryan, Lorna M.;Bazinet, Lauren;Habeshian, Kaiane A.;Cao, Shugeng;Clardy, Jon;Christensen, Kenneth A.;Rogers, Michael S.
通讯作者：
Rogers, Michael S.

A FRET-based high throughput screening assay to identify inhibitors of anthrax protective antigen binding to capillary morphogenesis gene 2 protein.

DOI：
10.1371/journal.pone.0039911
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Rogers MS;Cryan LM;Habeshian KA;Bazinet L;Caldwell TP;Ackroyd PC;Christensen KA
通讯作者：
Christensen KA

Targeting the anthrax receptors, TEM-8 and CMG-2, for anti-angiogenic therapy.

DOI：
10.2741/3806
发表时间：
2011-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
0
作者：
Cryan LM;Rogers MS
通讯作者：
Rogers MS

Spontaneous reversion of the angiogenic phenotype to a nonangiogenic and dormant state in human tumors.

人类肿瘤中血管生成表型自发回复为非血管生成和休眠状态。

DOI：
10.1158/1541-7786.mcr-13-0532-t
发表时间：
2014
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Rogers,MichaelS;Novak,Katherine;Zurakowski,David;Cryan,LornaM;Blois,Anna;Lifshits,Eugene;Bø,TrondH;Oyan,AnneM;Bender,EliseR;Lampa,Michael;Kang,Soo-Young;Naxerova,Kamila;Kalland,Karl-Henning;Straume,Oddbjorn;Akslen,LarsA;
通讯作者：