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

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通道广泛分布于全身，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)已被试验或提议用于治疗中风、癫痫、精神病、疼痛、创伤性脑损伤、下卡路性周期性瘫痪、哮喘、COPD、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、骨和前列腺癌)、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仍未得到开发。现有的BK通道调节剂还没有超过临床试验，并且存在效力和组织特异性差的问题。我们的长期目标是开发有效的人类BK通道的组织特异性调节剂。这些化合物在非靶组织中几乎没有不良反应，因此可以作为有效的治疗方法，也可以作为研究选定器官BK通道功能的重要研究工具。我们以前的研究和初步结果表明，BK通道调制器表现出不同的作用机制，这限制了传统的高通量筛选识别有用的调制器的能力。因此，该方案的目标是开发和验证一种创新的高通量筛选系统，能够检测和评估小分子调节剂的效力，这些小分子调节剂通过不同的作用机制发挥作用，并对不同组织中表达的BK通道变体具有选择性。该筛选包括突变BK通道的新颖使用，该通道的设计旨在提高分析的灵敏度，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、组织特异性的BK通道调节剂的几个关键障碍；并适用于筛选数十万种化合物。

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.