Cystic Fibrosis Corrector Ligands Discovered in CF Human Airway Cells

描述（由申请人提供）：在本拟定I期SBIR项目中，DiscoveryBioMed，Inc. (DBM)将继续建立在与伯明翰的亚拉巴马大学的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（Cl-）通道生理学家合作进行的积极项目的基础上。DBM开发了一种新的和简单的SPQ卤化物敏感染料和基于光的HTS药物发现计划，用于囊性纤维化（CF）。该“CF校正配体（CFCL）”计划的关键平台是对于最常见的CF突变（delF 508-CFTR突变）纯合的CF人支气管上皮细胞系。这个CF药物发现项目始于2007年秋季DBM的“预发布”阶段。迄今为止，DBM和合作者已经筛选了近10，000种小分子。“CFCL”分为两类具有治疗潜力的配体：（1）“delF 508-CFTR校正剂”和（2）“拯救Cl-通道增强剂”.“特定的delF 508- CFTR校正器由UAB的James Collawn和Zsuzsa Bebok博士验证和追求。上调分泌性Cl-转运（但不以生物化学方式拯救delF 508-CFTR）的拯救Cl-通道增强剂由DBM和Johns霍普金斯的Lihua Liang和Bill Guggino博士验证。该CF药物发现计划是一项新颖的综合评估，旨在广泛寻找任何和所有在人类细胞背景中具有疗效且可能具有CF治疗潜力的CFCL。囊性纤维化（CF）是一种遗传性疾病的肺和胃肠道系统，目前在儿童和年轻的成年人群体。尽管CF症状的治疗有所改善，但CF药物装备仍然缺乏攻击CF疾病的根本原因的治疗剂。该I期SBIR计划的首要目标是在CF人类气道细胞平台上发现新的CF校正剂配体，这将加速CF儿童和年轻人有意义的治疗。该CF第I阶段SBIR计划有两个里程碑。里程碑1将完成一项包含50，000种化合物的小分子筛选计划，以发现新型CFCL。在“delF 508-CFTR校正剂”和“拯救Cl-通道增强剂”这两个类别中，已经从命中CFCL中出现了命中列表和常见原子结构的支架。“作为里程碑1研究的延伸，DBM将在每筛选5,000种化合物后对潜在的命中化合物进行化学信息学分析，以告知命中小分子的验证和优先级。里程碑2将验证所有CFCL，将CFCL分为两个CF治疗类别，并将命中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将进行最终的详细化学信息学研究，并对未来最有效和最引人注目的热门CFCL进行药物化学研究。DBM将进行一项完整的细胞毒性分析，并在标准终点上评估主要CFCL对人肝、肾和肺细胞系的潜在毒性，作为计划的II期研究的体外前奏。这项工作的首要目标是确定最终可能转化为新疗法的小分子，这些新疗法将挽救CF肺和气道中的Cl-和液体转运，以使肺表面再水合，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，由于其进行性和使人衰弱的肺部疾病而导致死亡。盐和液体分泌的损失以及盐的加速吸收使气道脱水，并导致粘性粘液积聚，最终阻塞气流，导致CF患者的肺功能下降。我们的公司，Discovery BioMed，Inc.，寻求使用新的方法来发现CF校正剂配体，其恢复盐和水的分泌以预防和减弱CF肺病的发展。我们正在与两对CF专家合作，以验证这些至关重要和潜在的药物。

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.