CF Corrector Ligands Discovered on CF Human Airway Cells

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项目，该项目已进展到药物验证、优先排序和进展阶段。DBM的主要总体目标是通过完成重点药物发现项目和伴随的关键进展路径（利用疾病相关的人类细胞系统），确定用于治疗CF的新型临床候选CFTR校正配体（CFCLs）。这些化合物具有潜在的疾病改善作用，对疾病进展以及CF患者的健康和生活质量有显著影响。DBM、学术合作伙伴和行业顾问（在药物发现方面拥有70多年的经验）已经完善了二级验证和三级优先级分析及其在关键路径上的顺序，以便系统地识别最有效和“可药物化”的小分子，并朝着选择最佳化合物进行临床前开发的方向前进。第二阶段的目标将集中在从不同的化学支架中识别和“开发”最佳的含铅氯氟烃。这个CF药物发现项目是CF和其他慢性呼吸系统疾病的更大倡议的一部分，代表了DBM迄今为止最成熟的药物发现伞（见商业化计划）。对于这个修订后的ii期sbiri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，包括验证、优化和最终主要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 - Hit -to- Lead验证，这将描述新兴的Hit -to- Lead CF校正配体与第一阶段鉴定的有效基准先导化合物DBM 99H7的比较。里程碑2 -构效关系（SAR）开发和先导物优化，这将进一步分析和优化先导物CF校正化合物。里程碑3 -进一步分析先导化合物和选择临床候选化合物，这将确定临床前开发和临床试验的最佳化合物。具体目标，在每个关键里程碑下列出，在药物发现关键路径内编写关键实验任务；这些在其他地方的目标和里程碑以及研究策略部分有更详细的定义。它们代表了化合物的关键参数和特征，有助于确定最佳的cfcl。从机制上说，最理想的药物是既能“纠正”内质网delF508-CFTR的折叠缺陷，又能“激活或打开”分泌途径和顶质膜上delF508-CFTR的Cl-通道。额外的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Cl-通道，这些通道可能会放大顶端细胞膜中CFTR突变体的功能。DBM认为，其基准CFCL先导药物DBM 99H7是delF508-CFTR校正剂、delF508-CFTR开启剂和ENaC抑制剂的一个例子。在SBIR资助的第一阶段，通过对在CF人类气道细胞驱动药物发现项目中发现的CFCLs的初始先导和先导类别的研究，我们了解了许多最需要的先导药物的特征，以及如何最好地描述和发展它们。DBM有信心，这个二期项目将产生一个主要的CFCL临床候选药物，以及后备的CFCL，以推进到治疗开发的分拆公司，并最终获得生物制药的许可。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. 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.