CF Corrector Ligands Discovered on CF Human Airway Cells

描述(由申请人提供)：DiscoveryBioMed，Inc.(DBM)实现了SBIR的第一阶段里程碑，并寻求继续进行一项成熟的计划，该计划已进入药物验证、优先排序和进展阶段。S博士说，这项计划的主要总体目标是通过完成重点药物发现计划和伴随的关键进展路径，寻找治疗CF的新的临床候选CFTR校正配体(CFCL)，这些化合物利用与疾病相关的人体细胞系统。这些化合物具有潜在的疾病修改作用，对疾病进展以及CF患者的福祉和生活质量有显著影响。DBM、学术合作者和行业顾问(在药物发现方面拥有70年的经验)改进了二次验证和三次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“可用药”的小分子，并朝着选择最佳化合物(S)发展到临床前开发的方向前进。第二阶段的目标将集中于从不同的化学支架中识别和“进展”最好的含铅CFCL。该CF药物发现计划是针对CF和其他慢性呼吸道疾病的更大倡议的一部分，这些疾病代表了DBM S迄今为止最成熟的药物发现保护伞(见商业化计划)。对于这个修订的第二阶段SBIR驱动的计划应用，DBM提出了三个关键里程碑，这三个里程碑遵循药物发现关键路径的验证、优化，最终主要是吸入型临床候选化合物的选择(着眼于口服给药途径的二次检查)：里程碑1-Hit to Lead验证，这将描述新出现的Hit-to-Lead校正剂配体，并与第一阶段确定的有效基准铅化合物DBM 99H7进行比较。里程碑2-结构-活性关系(SAR)开发和铅优化，这将进一步剖析和优化铅CF校正剂化合物。里程碑3-先导化合物的进一步分析和临床候选药物的选择(S)，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，为药物发现关键路径中的关键实验任务编写脚本；这些目标在其他地方的目标和里程碑以及研究战略部分中有更详细的定义。它们代表了有助于识别最佳CFCL的化合物的关键参数和特征。从机理上讲，最理想的药物是一种既能“纠正”内质网内delF508-CFTR折叠缺陷，又能“激活或开放”分泌途径和顶端质膜上的delF508-CFTRCl-通道的药物。其他好处可能包括纠正其他失调的上皮细胞功能，如抑制过度活跃的上皮钠通道(ENaCs)，以及开放或上调其他可能放大顶端细胞膜突变CFTR功能的Cl-通道。DBM认为，其基准领先CFCL药物DBM 99H7是delF508-CFTR校正器、delF508-CFTR开放剂和ENaC抑制剂的一个例子。通过对第一阶段SBIR拨款中发现的CFCL的初始铅和铅类别的研究，我们了解了许多最需要的铅药物的特征，以及如何最好地描述和改进它们。DBM相信，这一第二阶段计划将产生一个主要的CFCL临床候选者，以及导致CFCL向前发展成为一家治疗开发衍生公司的后备CFCL，并最终通过BioPharma获得更多许可。DBM公司

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.