A Novel High Throughput Assay for Ion Channel Modulators

描述（由申请人提供）：离子通道占已知药物靶点的10- 20%，用于治疗包括心律失常、中风、高血压、心力衰竭、哮喘、囊性纤维化、癫痫、偏头痛、精神障碍、肌肉萎缩症和癌症在内的疾病。虽然离子通道提供了重要的治疗靶点，但它们通常是不需要的药物相互作用的焦点，导致潜在的严重副作用。心脏钾通道hERG是非预期药物相互作用的最常见靶点;阻断hERG可使个体易患心律失常、长QT综合征和心源性猝死。FDA建议，所有正在考虑用于研究性新药申请（IND）的药物都应在临床前研究中检测其对hERG钾通道的影响。由于药物开发成本的增加，制药公司在过程的早期阶段测试其化合物的hERG责任至关重要。最近的证据表明，药物诱导的hERG责任可能不仅来自通道的直接阻断，而且通过抑制hERG通道从其细胞内合成位点向细胞表面的移动。这种运输抑制导致细胞表面的功能通道减少。三氧化二砷和喷他脒，这两种药物目前都在临床上使用，以这种方式起作用，并与长QT综合征有关。目前用于确定hERG责任的方法都不能检测运输抑制剂。ChanXpress，Inc.开发了一种新的hERG责任的安全屏幕，这是最全面的可用。它使用专有技术检测通道阻滞剂和运输抑制剂，该技术使用基于抗体的荧光测定法监测hERG通道的表面表达。在第II阶段，我们将编制一个包含880种化合物的hERG责任数据库，其中包括hERG-Lite筛选沿着的结果以及膜片钳和蛋白质印迹数据。我们将在ChanXpress实现HERG-Lite检测的自动化，以便能够以比目前更高的通量提供给更多的客户。最后，ChanXpress将开发一种HERG-Lite试剂盒，其中包括细胞系，试剂和仪器选项，以便客户能够在自己的设施中进行该检测。HERG-Lite结合了快速、低成本、高通量和全面的hERG责任预测，是药物开发过程早期hERG责任筛查的首选检测方法。

DESCRIPTION (provided by applicant): Ion channels comprise 10-20 percent of known drug targets for diseases including cardiac arrhythmias, stroke, hypertension, heart failure, asthma, cystic fibrosis, epilepsy, migraine, mental disorders, muscular dystrophy, and cancer. While ion channels provide important therapeutic targets, they are often the focal point of unwanted drug interactions leading to potentially serious side effects. The cardiac potassium channel hERG is the most common target of undesired drug interactions; block of hERG can predispose individuals to cardiac arrhythmias, long QT syndrome, and sudden cardiac death. The FDA recommends that all drugs being considered for investigational new drug applications (IND) be tested for their effects on the hERG potassium channel in preclinical studies. Due to the increasing costs of drug development, it is crucial that pharmaceutical companies test their compounds for hERG liability at early stages in the process. Recent evidence indicates that drug-induced hERG liability can arise not just from direct block of the channel, but by inhibiting the movement of the hERG channel from its intracellular site of synthesis to the cell surface. This trafficking inhibition results in fewer functional channels at the cell surface. Arsenic trioxide and pentamidine, both of which are in clinical use today, act in this fashion and have been linked to long QT syndrome. None of the current methods for determining hERG liability are able to detect trafficking inhibitors. ChanXpress, Inc. has developed a novel safety screen for hERG liability that is the most comprehensive available. It detects both channel blockers and trafficking inhibitors using a proprietary technology that monitors surface expression of hERG channels using an antibody-based, chemiluminescent assay. In Phase II, we will compile a hERG liability database of 880 compounds that includes results from hERG-Lite screening along with patch clamp and Western blot data. We will automate the HERG-Lite assay at ChanXpress so that it can be offered to more clients with a higher throughput than is currently available. Finally, ChanXpress will develop a HERG-Lite kit that includes cell line, reagent, and instrumentation options so that clients are able to perform that assay at their own facility. The combination of speed, low cost, high throughput, and comprehensive hERG liability predictions position HERG-Lite as the premier assay for hERG liability screening early in the drug development process.