Development of a Novel High-Throughput Screening Platform for BK Channel Modulato

开发新型 BK 通道调制器高通量筛选平台

• 批准号: 8478440
• 负责人: FRANK T HORRIGAN
• 金额: $ 35.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478440
• 关键词: Adverse effects; Affect; Animal Model; Asthma; Biological Assay; Brain; Calcium; Cells; Chronic Obstructive Airway Disease; Clinical Trials; Complex; Data Set; Development; Diabetes Mellitus; Disease; Drug Targeting; Electrophysiology (science); Engineering; Epilepsy; Epithelial Cells; Erectile dysfunction; Exhibits; Glaucoma; Goals; Health; Human; Hypertension; Intestines; Ions; Irritable Bowel Syndrome; Life; Malignant Bone Neoplasm; Malignant neoplasm of brain; Membrane; Methods; Mining; Molecular Bank; Muscle Cells; Mutation; Myocardial Ischemia; Neurons; Organ; Overactive Bladder; Pain; Pancreatitis; Paralysed; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Physiology; Play; Point Mutation; Potassium; Potassium Channel; Process; Property; Prostate; Proteins; Psychotic Disorders; Regulation; Research; Resources; Rest; Rheumatoid Arthritis; Role; Secretory Cell; Signal Transduction; Specificity; Stomach; Stroke; Structure-Activity Relationship; System; Testing; Thallium; Therapeutic; Time; Tissues; Traumatic Brain Injury; United States National Institutes of Health; Urinary Incontinence; Variant; base; body system; bone; design; drug development; high throughput screening; improved; inhibitor/antagonist; innovation; large-conductance calcium-activated potassium channels; mutant; novel; novel strategies; patch clamp; programs; public health relevance; screening; sensor; small molecule; small molecule libraries; therapeutic target; tool; voltage

DESCRIPTION (provided by applicant): Potassium-conducting BK channels are attractive drug targets for the treatment of a wide variety of human disorders. Significant studies have shown that BK channels are distributed throughout the body and play important roles in a variety of physiological and disease processes. Compounds that inhibit or enhance BK channel function (modulators) have been tested or proposed to treat stroke, epilepsy, psychoses, pain, traumatic brain injury, hypokaleamic periodic paralysis, asthma, COPD, angina, arterial hypertension, ischemic heart disease, erectile dysfunction, urinary incontinence, gastric hypermotility, irritable bowel syndrome, pancreatitis, cancer (brain, bone, and prostate), rheumatoid arthritis, glaucoma and diabetes. However this diverse therapeutic potential remains largely untapped. Existing BK channel modulators have not advanced beyond clinical trials and suffer from poor potency and tissue specificity. Our long-term goal is to develop potent tissue-specific modulators of human BK channels. Such compounds should induce little to no adverse effects in non-target tissue, and therefore could serve as effective therapeutics as well as important research tools for the study of BK channel function in selected organs. Our previous research and preliminary results suggest that BK channel modulators exhibit diverse mechanisms of action which limit the ability of conventional high throughput screens to identify useful modulators. Therefore, the goal of this proposal is to develop and validate an innovative high throughput screening system, capable of detecting and evaluating the potency of small molecule modulators that act by different mechanisms of action and are selective for BK channel variants expressed in different tissues. The screen includes the novel use of mutant BK channels, engineered to increase the sensitivity of the assay to select modulators with the desired properties. The proposed screen will overcome several key barriers in the discovery and development of potent, tissue-specific BK channel modulators; and be suitable for screening hundreds of thousands of compounds.

描述（由申请人提供）：钾传导 BK 通道是治疗多种人类疾病的有吸引力的药物靶点。大量研究表明，BK通道分布于全身各处，在多种生理和疾病过程中发挥着重要作用。抑制或增强 BK 通道功能的化合物（调节剂）已被测试或建议用于治疗中风、癫痫、精神病、疼痛、创伤性脑损伤、低钾性周期性麻痹、哮喘、慢性阻塞性肺病、心绞痛、动脉高血压、缺血性心脏病、勃起功能障碍、尿失禁、胃动力亢进、肠易激综合征、 胰腺炎、癌症（脑癌、骨癌和前列腺癌）、类风湿性关节炎、青光眼和糖尿病。然而，这种多样化的治疗潜力在很大程度上尚未开发。现有的 BK 通道调节剂尚未通过临床试验，并且效力和组织特异性较差。我们的长期目标是开发人类 BK 通道的有效组织特异性调节剂。此类化合物对非靶组织几乎不会产生不良影响，因此可以作为有效的治疗药物以及研究选定器官中 BK 通道功能的重要研究工具。我们之前的研究和初步结果表明，BK 通道调制器表现出多种作用机制，这限制了传统高通量筛选识别有用调制器的能力。因此，本提案的目标是开发和验证一种创新的高通量筛选系统，能够检测和评估通过不同作用机制发挥作用并对不同组织中表达的 BK 通道变体具有选择性的小分子调节剂的效力。该筛选包括突变 BK 通道的新用途，该通道经过精心设计，可提高分析的灵敏度，以选择具有所需特性的调节剂。拟议的筛选将克服发现和开发有效的组织特异性 BK 通道调节剂的几个关键障碍；适合筛选数十万种化合物。