CF Corrector Ligands Discovered on CF Human Airway Cells

在 CF 人类气道细胞上发现 CF 校正配体

• 批准号: 8330822
• 负责人: Erik Mills Schwiebert
• 金额: $ 65.14万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330822
• 关键词: Apical; Attenuated; Back; Bacteria; Benchmarking; Biochemical; Biological Assay; Biological Products; Breathing; Cell membrane; Cell physiology; Cells; Characteristics; Chemicals; Chemistry; Child; Chronic; Clinical; Clinical Trials; Consultations; Critical Pathways; Cyclic AMP; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Development; Disease; Disease Progression; Doctor of Philosophy; Electrophysiology (science); Endoplasmic Reticulum; Environment; Epithelial; Epithelial Cells; Evaluation; Eye; Fluids and Secretions; Fluorescence; Forskolin; Functional disorder; Funding; Genistein; Glyburide; Goals; Grant; Human; In Vitro; Individual; Industry; Industry Collaborators; Lead; Learning; Licensing; Ligands; Location; Longevity; Lung; Lung diseases; Measures; Modeling; Molecular; Molecular Bank; Molecular Target; Morbidity - disease rate; Mucous body substance; Mutation; Nose; Oral Examination; Pathway interactions; Performance; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plant Roots; Premature Mortality; Process; Production; Proteins; Pulmonary Cystic Fibrosis; Quality of life; Recurrent disease; Research; Resistance; Rodent; Route; Safety; Selection Criteria; Series; Small Business Innovation Research Grant; Sodium Channel; Sodium Chloride; Staging; Structure of mucous membrane of nose; Structure-Activity Relationship; System; Testing; Toxic effect; Transgenic Mice; Up-Regulation; Validation; Work; absorption; apical membrane; base; commercialization; cystic fibrosis airway epithelia; cystic fibrosis patients; drug discovery; electrical measurement; epithelial Na+ channel; experience; in vivo; inhibitor/antagonist; meetings; monolayer; mutant; novel; patch clamp; pre-clinical; prevent; programs; response; scaffold; small molecule; therapeutic development; translational medicine; voltage; voltage clamp; young adult

DESCRIPTION (provided by applicant): DiscoveryBioMed, Inc. (DBM) achieved Phase 1 SBIR milestones and seeks to continue a mature program that has progressed to the hit-to-lead drug validation, prioritization and progression stage. DBM"s major over-arching goal for this program is to identify novel clinical candidate CFTR Corrector Ligands (CFCLs) for the treatment of CF through the completion of a focused Drug Discovery program and accompanying Critical Progression Path, which utilize disease-relevant human cell systems. These compounds have the potential to be disease-modifying with dramatic effects on disease progression as well as CF patients" well-being and quality of life. DBM, academic collaborators, and industry consultants (with >70 years experience in Drug Discovery) have refined secondary validation and tertiary prioritization assays and their order in a Critical Path such that the small molecules that are most potent and "druggable" are systematically identified and progressed forward towards selection of the best compound(s) for progression to Preclinical Development. Phase 2 aims will focus on identifying and "progressing" the best lead CFCLs from different chemical scaffolds. This CF Drug Discovery program is part of a larger initiative on CF and other chronic respiratory diseases that represent DBM"s most mature drug discovery umbrella to date (see Commercialization Plan). For this revised Phase 2 SBIR-driven program application, DBM proposes three key milestones, which follow a Drug Discovery Critical Path of validation, optimization and, ultimately, the selection of inhaled clinical candidate compounds primarily (with an eye on secondary examination of the oral route of administration): Milestone 1 - Hit to Lead Validation, which will profile emerging hit-to-lead CF corrector ligands in comparison to a potent benchmark lead compound identified in Phase 1, DBM 99H7. Milestone 2 - Structure-Activity Relationship (SAR) Development and Lead Optimization, which will profile further and optimize the lead CF corrector compounds. Milestone 3 - Further Profiling of Lead Compounds and Selection of Clinical Candidate(s), which will identify the best compounds for Preclinical Development and Clinical Trials. Specific aims, listed under each key milestone, script key experimental tasks within the Drug Discovery Critical Path; these are defined in more detail elsewhere in Goals and Milestones and Research Strategy sections. They represent key parameters and features of compounds that will assist with the identification of the best CFCLs. Mechanistically, the most desired drug is one that both "corrects" the folding defect in delF508-CFTR within the endoplasmic reticulum as well as "activates or opens" the delF508-CFTR Cl- channel in the secretory pathway and at the apical plasma membrane. Added benefits may include the correction of other dysregulated epithelial cell functions, such as inhibition of hyperactive epithelial sodium channels (the ENaCs) as well as the opening or up- regulation of other Cl- channels that might amplify mutant CFTR function in the apical cell membrane. DBM believes that its benchmark lead CFCL drug, DBM 99H7, is an example of a delF508-CFTR corrector, a delF508- CFTR opener, and an ENaC inhibitor. Through the study of initial lead and lead classes of CFCLs found in this CF human airway cell-driven drug discovery program during Phase1 of the SBIR grant, we have learned much about the features of lead drugs that are most desired and how to best profile and progress them. DBM is confident that this Phase 2 program will yield a primary CFCL clinical candidate as well as back-up lead CFCLs to progress forward into a therapeutic development spinout company and, ultimately, to out-license with a BioPharma. DBM, Inc.

描述（由申请人提供）：DiscoveryBiomed，Inc。（DBM）达到了第1阶段的SBIR里程碑，并试图继续一个成熟的计划，该计划已发展为命中率至铅的药物验证，优先级和进展阶段。该计划的DBM的主要超级目标是通过完成专注的药物发现计划的完成并随附的关键进展路径来确定新型临床候选CFTR CFTR CROCKER配体（CFCL），用于治疗CF，利用疾病中疾病的人类细胞系统的伴随。这些化合物具有疾病良好的疾病和疾病的影响。 DBM，学术合作者和行业顾问（具有70年的药物发现经验）精炼了二级验证和第三级优先测定测定法及其在临界路径中的订单，以至于最有效的和“可毒的小分子”是系统地鉴定出来的，并且可以向前鉴定出来，并朝着选择最佳化合物（S）进行良好的进步（S）。第2阶段的目标将集中于识别和“进步”不同化学支架的最佳铅CFCL。 This CF Drug Discovery program is part of a larger initiative on CF and other chronic respiratory diseases that represent DBM"s most mature drug discovery umbrella to date (see Commercialization Plan). For this revised Phase 2 SBIR-driven program application, DBM proposes three key milestones, which follow a Drug Discovery Critical Path of validation, optimization and, ultimately, the selection of inhaled clinical candidate compounds primarily (with an eye在对口服途径的次要检查中：里程碑1-命中率验证，与在第1阶段（dbm 99h7）中确定的有效的基准铅化合物相比，将介绍新兴的命中率cf prectot cof校正。以及临床候选者的选择，该临床候选者将确定临床前开发和临床试验的最佳化合物。具体目的，列出在每个关键里程碑下，脚本脚本关键实验任务关键路径中的脚本关键实验任务；这些在目标，里程碑和研究策略部分的其他地方更详细地定义。它们代表化合物的关键参数和功能，这些参数将有助于识别最佳CFCL。从机械上讲，最需要的药物是一种“纠正”内质网中DELF508-CFTR中的折叠缺陷，以及“激活或打开”分泌途径和顶端质膜膜上的DELF508-CFTR CL-通道。附加的好处可能包括校正其他失调的上皮细胞功能，例如抑制多活跃上皮钠通道（ENAC）以及其他CL-通道的开放或调节，这些CL通道可能会扩大可能在顶部细胞膜中扩增突变CFTR功能。 DBM认为其基准铅CFCL药物DBM 99H7是DELF508-CFTR校正器，DELF508-CFTR开瓶器和ENAC抑制剂的一个例子。通过研究SBIR Grant阶段1阶段的CF人类气道细胞驱动的药物发现程序中CFCL的初始铅和铅类别，我们对最需要的铅药物的特征有了很多了解，以及如何最佳概况和进步。 DBM有信心此阶段2计划将产生主要的CFCL临床候选者以及备用铅CFCL，以进步进入一家治疗性开发纺纱公司，并最终与生物武器交付许可。 DBM，Inc。