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: 8200582
• 负责人: Erik Mills Schwiebert
• 金额: $ 72.62万
• 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/8200582
• 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. PUBLIC HEALTH RELEVANCE: Cystic fibrosis is a progressive and debilitating lung disease that afflicts children and young adults; it causes significant morbidity and premature mortality with an average life-span of 32 years. Loss of salt and fluid secretion together with accelerated salt absorption dehydrates the airways and causes sticky mucus to accumulate. This accumulation eventually obstructs airflow, which leads to pulmonary decline in CF patients, and provides an ideal environment for infectious bacteria to colonize and cause recurrent disease exacerbations. DiscoveryBioMed, Inc., our team of academic partners from two national CF Research Centers, and industry consultant professionals derived from GlaxoSmithKline and AstraZeneca seek to garner continued funding to validate, prioritize and select the best CFTR corrector/opener ligands as new and effective CF drugs. Our program is discovering and 'progressing' compounds in CF human lung cell systems that restore normal function of multiple CF cell dysfunctions to attenuate and, ultimately, prevent the development of CF lung disease by attacking its root causes at the cellular and molecular level of the CF airways epithelium and the airway microenvironment. 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, Inc.

描述（由申请人提供）：DiscoveryBioMed，Inc. (DBM)实现了1期SBIR里程碑，并寻求继续一个成熟的计划，已进展到命中领先的药物验证，优先级和进展阶段。DBM对该项目的主要目标是通过完成一个集中的药物发现项目和伴随的关键进展路径，确定用于治疗CF的新型临床候选CFTR校正配体（CFCL），该项目利用疾病相关的人类细胞系统。这些化合物具有改善疾病的潜力，对疾病进展以及CF患者的健康和生活质量具有显著影响。DBM、学术合作者和行业顾问（在药物发现方面拥有超过70年的经验）已经完善了二级验证和三级优先级分析及其在关键路径中的顺序，以便系统地识别最有效和“可药用”的小分子，并朝着选择最佳化合物的方向发展，以进行临床前开发。第二阶段的目标将集中在确定和“发展”最好的铅CFCL从不同的化学支架。该CF药物发现计划是CF和其他慢性呼吸道疾病的更大计划的一部分，代表了DBM迄今为止最成熟的药物发现伞（见商业化计划）。对于这一修订后的2期SBIR驱动的项目申请，DBM提出了三个关键里程碑，它们遵循药物发现关键路径，即验证、优化和最终选择吸入临床候选化合物，（着眼于口服给药途径的二次检查）：里程碑1 -命中先导化合物验证，将与第1阶段DBM 99 H7中鉴定的有效基准先导化合物相比，描述新出现的命中先导化合物CF校正剂配体。里程碑2 -结构-活性关系（SAR）开发和先导化合物优化，这将进一步分析和优化先导CF校正剂化合物。里程碑3 -进一步分析先导化合物和选择临床候选化合物，这将确定用于临床前开发和临床试验的最佳化合物。在每个关键里程碑下列出的具体目标，描述了药物发现关键路径中的关键实验任务;这些在目标和里程碑以及研究策略部分的其他地方进行了更详细的定义。它们代表了化合物的关键参数和特征，将有助于确定最佳CFCL。从机制上讲，最需要的药物是既“纠正”内质网内delF 508-CFTR的折叠缺陷又“激活或打开”分泌途径中和顶端质膜处的delF 508-CFTR Cl-通道的药物。额外的益处可以包括校正其他失调的上皮细胞功能，例如抑制过度活跃的上皮钠通道（ENaC）以及打开或上调可能放大顶端细胞膜中突变CFTR功能的其他Cl-通道。DBM认为，其基准领先的CFCL药物DBM 99 H7是delF 508-CFTR校正剂，delF 508- CFTR开放剂和ENaC抑制剂的一个例子。通过对SBIR资助第1阶段CF人类气道细胞驱动药物发现计划中发现的CFCL的初始铅和铅类的研究，我们已经了解了很多关于最需要的铅药物的特征以及如何最好地描述和进展它们。DBM相信，这个第二阶段计划将产生一个主要的CFCL临床候选人以及备份领导CFCL前进到一个治疗开发分拆公司，并最终与生物制药许可证。DBM公司 公共卫生相关性：囊性纤维化是一种进行性和使人衰弱的肺部疾病，折磨儿童和年轻人;它导致显著的发病率和过早死亡率，平均寿命为32岁。盐和液体分泌的损失以及盐吸收的加速使气道脱水并导致粘性粘液积聚。这种积聚最终阻碍气流，导致CF患者的肺功能下降，并为感染性细菌定植和导致复发性疾病恶化提供了理想的环境。DiscoveryBioMed，Inc.，我们的团队来自两个国家CF研究中心的学术合作伙伴，以及来自葛兰素史克和阿斯利康的行业顾问专业人士寻求获得持续的资金，以验证，优先考虑和选择最好的CFTR校正剂/开放剂配体作为新的有效的CF药物。我们的计划是在CF人类肺细胞系统中发现和“发展”化合物，这些化合物可以恢复多种CF细胞功能障碍的正常功能，以减弱并最终通过在CF气道上皮和气道微环境的细胞和分子水平上攻击其根本原因来预防CF肺病的发展。这些化合物具有改善疾病的潜力，对疾病进展以及CF患者的健康和生活质量具有显著影响。DBM公司