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Discovery of Cell-based Chemical Probes Targeting Aberrant Angiogenesis in the Eye

发现针对眼部异常血管生成的基于细胞的化学探针

基本信息

批准号：
10610440
负责人：
Donna M Huryn
金额：
$ 15.55万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610440
关键词：
3-Dimensional Actin-Binding Protein Actins Address Affinity Age related macular degeneration Alternative Therapies Angiogenesis Inhibitors Binding Biochemical Biochemistry Bioinformatics Biological Assay Biological Testing Blindness Blood Vessels Calorimetry Cell Proliferation Cells Cellular Assay Cellular biology Chemicals Choroid Clinical Computer Models Critical Pathways Cytoskeleton Data Development Diabetic Retinopathy Disease Disease Progression Dose Drug Design Endothelium Evaluation Exhibits Eye Eye diseases Future Goals Heart Image Analysis In Vitro Individual Investigation Lead Ligation Mediator Modeling Modification Morphogenesis Ocular Pathology Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Play Polymers Process Property Reproducibility Resistance Retina Retinal Diseases Retinopathy of Prematurity Role Route Series Signal Transduction Structure Structure-Activity Relationship Synthesis Chemistry Titrations Toxic effect Treatment Factor Update Validation Variant Vascular Endothelial Cell Vascular Endothelial Growth Factors analog angiogenesis antagonist cell motility cheminformatics clinical candidate cytotoxicity design improved in vivo in vivo Model inhibitor meter mouse model novel novel therapeutics ophthalmic drug patient population polymerization prevent process optimization profilin proliferative diabetic retinopathy protein protein interaction response retinal angiogenesis scaffold screening small molecule structural biology synergism targeted treatment thymosin beta(4)

项目摘要

Project Summary/Abstract Proliferative diabetic retinopathy, wet age-related macular degeneration, and retinopathy of prematurity are all diseases of the eye that can lead to blindness and are due to abnormal development of retinal or choroid blood vessels. Although intravitreal anti-angiogenic therapies targeting vascular endothelial growth factor signaling are generally effective for these diseases, spontaneous or acquired resistance is a significant problem and points to the need for high-quality cell-based chemical probes for interrogating angiogenic pathways and developing alternative therapies. To address this unmet need, we propose developing high-quality cell-based chemical probes for the profilin1 (Pfn1)-actin protein-protein interaction. Pfn1 is critical for angiogenesis as it plays a vital role in the dynamic remodeling of the actin cytoskeleton in response to angiogenic signals. We have shown in numerous contexts that inhibition or suppression of Pfn1 leads to reduced angiogenesis and have recently demonstrated that inhibiting Pfn1 reduces the formation of new blood vessels in both ex vivo and in vivo models of retinopathy. We have already identified a validated hit compound that inhibits the Pfn1-actin interaction in biochemical and cell-based assays and confirmed its target engagement in cells. To increase the potency of this inhibitor while maintaining drug-like properties, we will employ an iterative optimization process that will be guided by our structural and cheminformatic models and by the structure- activity relationship that will be developed around the key points of variation during each iteration of compound selection, synthesis, and biological testing. Derivatives will be evaluated in a gated assay cascade to determine their binding affinity for Pfn1 and activity in cells. This iterative process aims to identify an inhibitor of the Pfn1- actin interaction with sub-micromolar potency in both biochemical and cellular assays. Compounds that meet well-defined criteria for novelty and potency in our first round of assays will be validated in the second series of assays to confirm target engagement, selectivity, and other functional utilities (e.g., synergy with an anti- VEGF agent and barrier-function modulatory agent). Successful completion of these studies will result in a potent and specific inhibitor of Pfn1-actin for studying the role of Pfn1 in aberrant angiogenesis and may ultimately lead to a clinical candidate for the treatment of eye disease.

项目总结/摘要糖尿病视网膜病变、湿性年龄相关性黄斑变性和早产儿视网膜病变都是由于视网膜或脉络膜血液的不正常发展而导致失明的眼病船舶.尽管靶向血管内皮生长因子信号传导的玻璃体内抗血管生成疗法通常对这些疾病有效，自发或获得性抗性是一个重要的问题，指出需要高质量的基于细胞的化学探针来询问血管生成途径，开发替代疗法为了解决这一未满足的需求，我们建议开发高质量的基于细胞的用于profilin 1（Pfn 1）-肌动蛋白蛋白-蛋白质相互作用的化学探针。Pfn 1对血管生成至关重要，因为它在响应血管生成信号的肌动蛋白细胞骨架的动态重塑中起重要作用。我们已经在许多情况下表明，Pfn 1的抑制或阻遏导致血管生成减少，最近已经证明，抑制Pfn 1可以减少体外和体外新血管的形成，和视网膜病的体内模型。我们已经发现了一种有效的化合物， pfn 1-肌动蛋白相互作用的生物化学和细胞为基础的分析，并证实其在细胞中的目标参与。到增加这种抑制剂的效力，同时保持药物样特性，我们将采用迭代优化过程将由我们的结构和化学信息模型以及结构- 在化合物的每次迭代期间围绕变化的关键点开发的活性关系选择、合成和生物测试。将在门控试验级联中评价衍生物，以确定它们对Pfn 1的结合亲和力和在细胞中的活性。该迭代过程旨在鉴定Pfn 1的抑制剂- 肌动蛋白相互作用的亚微摩尔效力在生化和细胞测定。化合物满足在我们的第一轮试验中，新奇和效力的明确标准将在第二轮试验中得到验证用于确认靶接合、选择性和其它功能性效用（例如，与抗- VEGF剂和屏障功能调节剂）。成功完成这些研究将导致 Pfn 1-肌动蛋白的有效和特异性抑制剂，用于研究Pfn 1在异常血管生成中的作用，最终导致用于治疗眼病的临床候选物。