Chronically Acting CFTR Inhibitor Discovery for Secretory Diarrhea and ADPKD

发现治疗分泌性腹泻和 ADPKD 的慢性 CFTR 抑制剂

• 批准号: 8646016
• 负责人: Deborah Mai
• 金额: $ 22.47万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646016
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Area; Automation; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Biological; Biological Assay; Biological Factors; Biological Process; Birth; Cause of Death; Cell Culture Techniques; Cell Line; Cell membrane; Cell physiology; Cells; Chemicals; Child; Childhood; Chloride Channels; Chloride Ion; Chlorides; Clinical; Collection; Complement; Critical Pathways; Cystic Fibrosis; Data; Development; Diarrhea; Disease; Disease Progression; Ensure; Epithelial Cells; Epithelium; Evaluation; FDA approved; Fluids and Secretions; Funding; Future; Goals; HT29 Cells; Healthcare; Hereditary Disease; Housing; Human; Hyperactive behavior; Impairment; In Vitro; Incidence; Infection; Intestines; Kidney Diseases; Knowledge; Laboratories; Lead; Libraries; Ligands; Link; Malaria; Measles; Measurement; Mediating; Membrane; Metabolic; Modification; Molecular; Molecular Bank; Oral Rehydration Therapy; Pathogenesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Philosophy; Physiological; Physiological Processes; Play; Preclinical Drug Evaluation; Public Health; Regulation; Renal function; Research; Research Infrastructure; Resources; Rest; Risk; Role; Savings; Series; Severities; Small Business Innovation Research Grant; Staging; Symptoms; Testing; Therapeutic; Up-Regulation; Validation; Vision; Work; base; bone; candidate selection; cost effective; counterscreen; design; drug candidate; drug discovery; global health; in vivo; inhibitor/antagonist; innovation; interest; killings; loss of function mutation; monolayer; novel; programs; public health relevance; respiratory; screening; small molecule; tool

Project Summary Abstract DiscoveryBioMed, Inc. (DBM) has launched an innovative and automation-friendly drug discovery program to screen a collection of small molecular compounds on a human epithelial cell platform expressing physiologically relevant levels of the wild-type Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to discover a new class of therapeutic drugs for secretory diseases. CFTR plays a critical role in the regulation of Cl- transport and fluid secretion such that hyperactivity of the CFTR Cl- channel results in uncontrolled fluid secretion. Two CFTR-mediated diseases, secretory diarrhea and Autosomal Dominant Polycystic Kidney Disease (ADPKD), are driven in part by chronically active CFTR. These diseases demand treatment options that are effective and readily available due to their widespread impact on public health. Diarrheal illnesses are a leading cause of death worldwide. Despite the accepted practice of oral rehydration therapy, the incidence of secretory infection remains alarmingly high; and, thus, there is a constant need to develop drugs that alleviate diarrheal symptoms. The need to find therapeutic options for ADPKD is even more urgent due to a complete lack of FDA-approved drugs available for the nearly 12.5 million people suffering from this kidney disease. DBM recognizes the severity of these clinical problems and has focused our drug discovery efforts in developing an innovative program that would not only provide possible therapeutic options for the aforementioned diseases, but would also allow for the mechanistic study of CFTR function in the pathogenesis of CFTR-mediated diseases, which is also currently limited. The novelty in this drug discovery program depends on the use of a biologically relevant human cell platform that expresses the disease-relevant target, wild-type CFTR. DBM embodies the philosophy of 'humanized' drug discovery to increase disease relevance while decreasing risk in advanced stages of de novo drug screening. It is this core principle that reflects DBM's unique angle, approach, and offering to the drug discovery space. For this SBIR Phase I application, DBM presents a series of methodical and focused steps that will aid in the successful completion of this proposal and are outlined by the following Milestones: 1) Develop and implement a novel drug discovery platform with human CFBE cells expressing wild-type CFTR to detect potent compounds inhibiting CFTR-mediated Cl- secretion, 2) Perform de novo HTS of 75,000 small molecular compounds for the discovery of novel CFTR inhibitors, 3) Validate putative hits as delineated by a robust Critical Path, 4) Establish physiological relevance for validated hits for ADPKD and secretory diarrhea, and 5) Perform chemoinformatics on validated hits for the identification of hit-to-lead chemical classes for drug candidate selection and deeper chemical profiling. As an added benefit, DBM has existing internal CF and ADPKD programs which provide a unique infrastructure of valuable expertise and resources to help accomplish all Milestones and projected goals. A preliminary proof- of-concept screen of >5% of the total compound library has been completed, where validated hits and compounds of interest are now being tested in advanced stages within the Critical Path. DBM seeks SBIR funds to deepen and accelerate this critical CFTR inhibitor drug discovery program.

项目摘要摘要 DiscoveryBioMed，Inc.(DBM)启动了一项创新的、自动化友好的药物发现计划，以 在人上皮细胞平台上筛选表达小分子化合物 野生型囊性纤维化跨膜电导调节器的生理相关水平 发现一类治疗分泌性疾病的新药物。CFTR在监管中发挥着关键作用 氯离子的运输和液体分泌，使得CFTRCl-通道的过度活动导致液体失控 分泌物。分泌性腹泻和常染色体显性遗传性多囊肾两种CFTR型疾病 疾病(ADPKD)在一定程度上是由长期活跃的CFTR驱动的。这些疾病需要多种治疗方案 由于它们对公共卫生的广泛影响，它们是有效的和容易获得的。腹泻病是 是世界范围内的主要死因。尽管口服补液疗法是公认的做法，但 分泌性感染仍然居高不下；因此，需要不断地开发减轻 腹泻症状。为ADPKD寻找治疗方案的需要更加迫切，因为 近1250万患有这种肾脏疾病的患者缺乏FDA批准的药物。 DBM认识到这些临床问题的严重性，并将我们的药物发现工作集中在 开发一种创新的计划，不仅为患者提供可能的治疗选择 上述疾病，但也将允许对CFTR功能在发病机制中的研究 目前也是有限的。这个药物发现计划的新颖性 取决于表达疾病相关靶点的生物相关人类细胞平台的使用， 野生型cftr。DBM体现了人性化药物发现的理念，以增加与疾病的相关性 同时降低新药筛选晚期阶段的风险。正是这一核心原则反映了DBM的 为药物发现空间提供独特的角度、方法和服务。对于此SBIR第一阶段应用，DBM 提出了一系列有条不紊和有重点的步骤，将有助于成功完成本提案 并概述了以下里程碑：1)开发和实施具有以下特点的新药发现平台 表达野生型cftr的人CFBE细胞检测抑制cftr介导的氯离子的有效化合物 分泌物，2)对75,000个小分子化合物进行从头HTS，以发现新的CFTR 抑制剂，3)验证由健壮的关键路径描述的假定的命中，4)建立生理相关性 对于ADPKD和分泌性腹泻的验证命中，以及5)对验证的命中执行化学信息学 确定用于候选药物选择和更深层次化学分析的Hit-to-Lead化学类别。作为一种 额外的好处是，DBM拥有现有的内部CF和ADPKD计划，这些计划为 宝贵的专业知识和资源，以帮助实现所有里程碑和计划目标。初步的证据是- 已完成化合物库总数的5%的概念筛选，其中验证的命中率和 目前正在关键路径内的高级阶段对感兴趣的化合物进行测试。DBM寻求SBIR 资金，以深化和加快这一关键的CFTR抑制剂药物发现计划。