Cystic Fibrosis Corrector Ligands Discovered in CF Human Airway Cells

在 CF 人类气道细胞中发现囊性纤维化校正配体

• 批准号: 7748575
• 负责人: Erik Mills Schwiebert
• 金额: $ 32.2万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748575
• 关键词: Alabama; Attenuated; Biochemical; Biochemistry; Biological Assay; Biological Factors; Categories; Cell Line; Cell model; Cell physiology; Cells; Child; Childhood; Chloride Ion; Chlorides; Collaborations; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Development; Disease; Doctor of Philosophy; Dyes; Enhancers; Epithelial Cells; Fluids and Secretions; Fluorescence; Generations; Goals; Human; In Vitro; Inherited; Kidney; Lead; Libraries; Ligands; Light; Liquid substance; Liver; Lung; Lung diseases; Methods; Molecular Bank; Molecular Target; Mucociliary Clearance; Mucous body substance; Mutation; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plant Roots; Population; Process; Pulmonary Cystic Fibrosis; Research; Research Personnel; Robotics; Screening procedure; Small Business Innovation Research Grant; Sodium Chloride; Source; Structure; Surface; Symptoms; Testing; Therapeutic; Toxic effect; Universities; Validation; Water; Work; absorption; abstracting; base; cheminformatics; cystic fibrosis airway; cystic fibrosis patients; design; drug discovery; falls; gastrointestinal system; improved; medical schools; meetings; monolayer; mortality; novel; novel therapeutics; prevent; programs; public health relevance; scaffold; small molecule; trafficking; young adult

DESCRIPTION (provided by applicant): In this proposed Phase I SBIR program, DiscoveryBioMed, Inc. (DBM) will continue to build upon an active project performed in collaboration with CFTR cell biologists at the University of Alabama at Birmingham and alternative rescue chloride (Cl-) channel physiologists at Johns Hopkins University School of Medicine. DBM developed a novel and simple SPQ halide-sensitive dye- and light-based HTS drug discovery program for cystic fibrosis (CF). The key platform for this "CF corrector ligand (CFCL)" program is a CF human bronchial epithelial cell line homozygous for the most common CF mutation, the delF508-CFTR mutation. This CF drug discovery project began during the "pre-launch" phase for DBM in Fall 2007. DBM and collaborators have screened almost 10,000 small molecules to date. "CFCLs" have fallen into two categories of ligands with therapeutic potential: (1) "delF508-CFTR correctors" and (2) "rescue Cl- channel enhancers." Specific delF508- CFTR correctors are validated and pursued by Drs. James Collawn and Zsuzsa Bebok at UAB. Rescue Cl- channel enhancers that up-regulate secretory Cl- transport (but do not rescue delF508-CFTR biochemically) are validated by DBM and by Drs. Lihua Liang and Bill Guggino at Johns Hopkins. This CF drug discovery program is a novel, comprehensive assessment that casts a wide net to find any and all CFCLs that have efficacy in a human cell background and that may have CF therapeutic potential. Cystic fibrosis (CF) is an inherited disease of the pulmonary and gastrointestinal systems that presents in pediatric and young adult populations. Despite an improvement in the treatment of CF symptoms, the CF drug armament still lacks therapeutics that attack the root causes of CF disease. The over-arching goal of this Phase I SBIR program is that novel CF corrector ligands will be discovered on a CF human airway cell platform that will accelerate the march toward meaningful treatment for CF children and young adults. This CF Phase I SBIR program has 2 milestones. Milestone 1 will complete a small molecule screening program of 50,000 compounds to discover novel CFCLs. Hit lists and scaffolds of common atomic structure have already emerged from the hit CFCLs in both categories of "delF508-CFTR correctors" and "rescue Cl- channel enhancers." As an extension of Milestone 1 research, DBM will perform cheminformatic analysis of potential hit compounds after each 5,000 compounds screened to inform the validation and prioritization of the hit small molecules. Milestone 2 will validate all CFCLs, differentiate the CFCLs into the two CF therapeutic categories, and assign the hit CFCLs to each pair of academic partners for further study. As an extension of Milestone 2 research, DBM will perform final detailed cheminformatics and perform medicinal chemistry on the most potent and compelling hit lead CFCLs going forward. DBM will perform a complete cell toxicity analysis as well as assess potential toxicity of the lead CFCLs on human liver, kidney and lung cell lines on standard endpoints as an in vitro prelude to planned Phase II research. The over-arching goal of this work is to identify small molecules that may eventually be transformed into new therapeutics that will rescue lose Cl- and fluid transport in the CF lung and airways to re-hydrate lung surfaces and aid impaired mucociliary clearance in CF disease. PUBLIC HEALTH RELEVANCE: Cystic fibrosis is a disease of children and young adults that causes mortality due to its progressive and debilitating lung disease. Loss of salt and fluid secretion and accelerated absorption of salt dehydrates the airways and cause sticky mucus accumulation that eventually obstructs airflow leading to pulmonary decline in CF patients. Our company, DiscoveryBioMed, Inc., seeks to use novel methods to discover CF corrector ligands that restore salt and water secretion to prevent and attenuate the development of CF lung disease. We are partnering with two pairs of CF experts to validate these critically important and potential drugs.

描述（由申请人提供）：在这个拟议的I期SBIR项目中，DiscoveryBioMed, Inc. （DBM）将继续与阿拉巴马大学伯明翰分校的CFTR细胞生物学家和约翰霍普金斯大学医学院的替代救援氯离子（Cl-）通道生理学家合作开展一个积极的项目。DBM开发了一种新颖而简单的SPQ卤化物敏感染料和光基HTS药物发现项目，用于治疗囊性纤维化（CF）。这个“CF校正配体（CFCL）”程序的关键平台是最常见的CF突变delF508-CFTR突变的CF人支气管上皮细胞系纯合子。这个CF药物发现项目开始于2007年秋季DBM的“上市前”阶段。迄今为止，DBM及其合作者已经筛选了近1万个小分子。“CFCLs”分为两类具有治疗潜力的配体：(1)“delF508-CFTR校正剂”和(2)“拯救Cl-通道增强剂”。特定的delF508- CFTR校正器由博士验证和追求。UAB的James Collawn和Zsuzsa Bebok。援救Cl-通道增强剂上调分泌Cl-转运（但不援救delF508-CFTR）已被DBM和dr。约翰霍普金斯大学的Lihua Liang和Bill Guggino。这个CF药物发现项目是一个新颖的、全面的评估，它广泛地寻找任何和所有在人类细胞背景下有效的cfcl，并可能具有CF治疗潜力。囊性纤维化（CF）是一种肺部和胃肠道系统的遗传性疾病，常见于儿科和青年人群。尽管对CF症状的治疗有所改善，但CF药物武器仍然缺乏针对CF疾病根源的治疗方法。这个I期SBIR项目的首要目标是在CF人类气道细胞平台上发现新的CF校正配体，这将加速CF儿童和年轻人有意义治疗的进程。CF I期SBIR项目有2个里程碑。里程碑1号将完成5万种化合物的小分子筛选项目，以发现新型cfcl。在“delF508-CFTR校正剂”和“救援Cl-通道增强剂”这两类受打击的cfcl中，已经出现了常见原子结构的攻击列表和支架。作为里程碑1研究的延伸，DBM将在每筛选5000种化合物后对潜在的靶向化合物进行化学信息学分析，以告知靶向小分子的验证和优先级。里程碑2将验证所有cfcl，将cfcl区分为两种CF治疗类别，并将成功的cfcl分配给每对学术合作伙伴进行进一步研究。作为里程碑2研究的延伸，DBM将对最有效和最引人注目的先导cfcl进行最终的详细化学信息学和药物化学研究。DBM将进行完整的细胞毒性分析，并在标准终点上评估含铅cfcl对人类肝脏、肾脏和肺细胞系的潜在毒性，作为计划中的II期研究的体外前奏。这项工作的首要目标是确定可能最终转化为新疗法的小分子，这些小分子将挽救CF肺和气道中丢失的Cl-和液体运输，以重新水化肺表面，并帮助CF疾病中受损的粘膜纤毛清除。公共卫生相关性：囊性纤维化是一种儿童和年轻人的疾病，由于其进行性和衰弱性肺部疾病而导致死亡。盐和液体分泌的损失以及盐的吸收加速使气道脱水，并引起粘性粘液积聚，最终阻碍气流，导致CF患者肺功能下降。我们的公司DiscoveryBioMed， Inc.寻求使用新方法发现CF校正配体，恢复盐和水的分泌，以预防和减轻CF肺部疾病的发展。我们正在与两对CF专家合作，验证这些至关重要的潜在药物。