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Chemical Optimization of c-Cbl Antagonists for Corneal Wound Healing

用于角膜伤口愈合的 c-Cbl 拮抗剂的化学优化

基本信息

批准号：
10557187
负责人：
BRIAN P. CERESA
金额：
$ 38.5万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557187
关键词：
Acceleration Address Advanced Development Affinity Anatomy Animal Model Antineoplastic Agents Bacteria Binding Biochemical Biological Assay Biology Biomedical Engineering Blindness Bypass Calorimetry Cell Proliferation Cell model Cetuximab Chemical Injury Chemical Structure Chemicals Complex Cornea Corneal Diseases Corneal Injury Data Development Diabetes Mellitus Disease Distress Drug Side Effects Drug usage EGF gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Epithelium Event Eye Eye Infections FDA approved Generations Goals Growth Factor Receptors Health care facility Homeostasis Human In Vitro Incidence Infection Investigation Laboratories Lead Ligands Light Lysosomes Maintenance Measures Mediating Membrane Mission Modeling Modification Molecular Operative Surgical Procedures Oryctolagus cuniculus Pain Patients Prevalence Primary Care Procedures Proliferating Proteins Public Health Reagent Receptor Signaling Recombinants Recurrence Research Retina Rodent Signal Transduction Structure Testing Therapeutic Therapeutic Agents Tissue Model Tissues Topical application Trauma Virus Vision Work antagonist cancer type cell growth cell motility cell replacement therapy corneal epithelial wound healing corneal epithelium corneal surgery cytokine cytotoxicity desensitization drug development drug-like compound experience heat injury improved in silico in vivo inhibitor innovation interest knock-down limbal nanomolar novel novel therapeutics particle pharmacologic preservation prevent receptor restoration side effect stem cell replacement tissue culture trafficking ubiquitin-protein ligase wound healing

项目摘要

Project Summary An intact and fully differentiated corneal epithelium is critical for proper vision and to keep foreign objects (bacteria, viruses, small particles) out of the eye. However, damage to the corneal epithelium is one of the most common ocular problems presented in primary care facilities and arises from a variety of factors, including trauma, disease, and a side-effect of drugs. Despite the prevalence, discomfort, and potential for blindness associated with perturbation of the corneal epithelium, there are no FDA-approved agents that promote the restoration and homeostasis of this tissue. The long-term goal of our research is to develop new compounds that promote corneal epithelial wound healing and homeostasis. The overall objective of this application is to chemically optimize a recently identified c-Cbl antagonist to increase its affinity and potency, while decreasing cytotoxicity. To accomplish this, we will test the central hypothesis that compounds that disrupt EGFR:c-Cbl interactions will prevent EGFR ubiquitylation, divert the activated EGFR from the lysosome, and prolong EGFR signaling. Based on preliminary studies, this prolongs EGFR activity and increases the restoration and maintenance of corneal epithelium via cell migration, proliferation, and differentiation. The rationale for these studies is that knockdown of c-Cbl and inhibits EGFR ubiquitylation, prolongs EGFR activity, and enhances corneal epithelial wound healing. Following an in silico screen of 25,000,000 compounds, we have identified several lead compounds that bind c-Cbl and inhibit ligand-mediated EGFR ubiquitylation. We seek to develop the top compound into a therapeutic agent with the following specific aims. In Aim 1, we will structurally optimize our lead compound to increase its affinity for c-Cbl and disrupt EGFR:c-Cbl binding. Multiple rounds of chemical modifications to our lead compound will be used to identify new derivatives that bind recombinant c-Cbl with high affinity and disrupt EGFR:c-Cbl interactions. In Aim 2, we will test the highest affinity compounds for disruption of c-Cbl-mediated ubiquitylation and trafficking of the EGFR. The top candidates will be tested for their ability to block ligand-mediated EGFR ubiquitylation and lysosomal degradation, and if they prolong EGFR signaling in corneal epithelial cells. In Aim 3, we will determine whether inhibitors of EGFR ubiquitylation promote corneal epithelial wound healing. The top compounds will be assayed for corneal epithelial wound healing using in vitro, ex vivo, and in vivo assays. Our proposed studies are innovative, in our opinion, because we will by-pass the limitation of EGFR occupancy and target a novel protein (c-Cbl) and molecular mechanism (receptor desensitization). These studies are significant because accelerating re-epithelialization and homeostasis of compromised corneas will decrease patient distress, minimize infections, and reduce the incidence of blindness. Corneal epithelial homeostasis is a major public health issue with limited treatments. Our goal is to develop our lead compounds for the topical treatment of compromised corneal epithelium to restore tissue homeostasis.

项目摘要完整和完全分化的角膜上皮对于正常视力和保存异物至关重要。 (细菌、病毒、小颗粒)从眼睛里流出。然而，对角膜上皮的损伤是最常见的眼部问题出现在初级保健机构，并由各种因素引起，包括创伤、疾病和药物的副作用。尽管患病率、不适感和潜在的与角膜上皮扰动相关的失明，目前还没有FDA批准的药物可以促进这一组织的修复和动态平衡。我们研究的长期目标是开发新的促进角膜上皮伤口愈合和动态平衡的化合物。这样做的总体目标是应用是对最近发现的c-Cbl拮抗剂进行化学优化以增加其亲和力和效力，同时降低细胞毒性。为了实现这一点，我们将测试中心假设，即合成破坏EGFR：C-Cbl相互作用将阻止EGFR泛素化，将激活的EGFR从溶酶体中转移出来，并延长EGFR信号转导。根据初步研究，这延长了EGFR的活性，并增加了通过细胞迁移、增殖和分化恢复和维持角膜上皮。这个这些研究的基本原理是，c-Cb1基因被敲除并抑制EGFR泛素化，延长EGFR活性，并促进角膜上皮伤口愈合。在对25,000,000种化合物进行电子筛查后，我们已经确定了几种与c-Cbl结合并抑制配体介导的EGFR泛素化的先导化合物。我们寻求将顶级化合物开发为具有以下特定目标的治疗剂。在目标1中，我们将从结构上优化我们的先导化合物，以增加其对c-Cbl的亲和力，并破坏EGFR：C-Cbl结合。我们将对先导化合物进行多轮化学修饰，以确定新的衍生产品高亲和力结合重组c-Cbl，破坏EGFR：C-Cbl相互作用。在目标2中，我们将测试最高用于破坏c-Cbl介导的泛素化和EGFR运输的亲和化合物。顶层候选人将接受测试，以确定他们是否有能力阻止配体介导的EGFR泛素化和溶酶体如果他们延长了角膜上皮细胞中的EGFR信号。在目标3中，我们将确定是否 EGFR泛素化抑制剂促进角膜上皮损伤愈合。最重要的化合物将是用体外、体外和体内实验检测角膜上皮损伤愈合情况。我们建议的研究在我们看来，是创新的，因为我们将绕过EGFR入住率的限制，瞄准一部新的蛋白质(c-Cbl)和分子机制(受体脱敏)。这些研究具有重要意义，因为加速受损角膜的再上皮化和动态平衡将减少患者的痛苦，最大限度减少感染，降低失明发生率。角膜上皮细胞动态平衡是一种主要的公众有限的治疗带来的健康问题。我们的目标是开发我们的先导化合物，用于局部治疗受损的角膜上皮以恢复组织动态平衡。