CFTR inhibitors for therapy of polycystic kidney disease

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）：转化科学和特定的挑战主题，15- DK-103：将NIDDK疾病发病机制中的新分子和途径的发现转化为潜在的治疗、诊断或研究工具。多囊肾是人类最常见的遗传性疾病之一，也是慢性肾功能不全需要透析或肾移植的主要原因。有令人信服的证据表明，在常染色体显性遗传性多囊肾病（ADPKD）中，进行性液体蓄积到囊肿中需要囊性纤维化跨膜传导调节蛋白（CFTR）分泌氯，CFTR是一种cAMP调节的氯离子通道，当突变时，会导致遗传性疾病囊性纤维化。ADPKD的囊肿生长需要液体分泌到囊肿腔内，并伴有上皮细胞增生。CFTR抑制剂“抗分泌治疗”可能提供终身治疗，以延长ADPKD患者的肾脏存活。目前还没有FDA批准的药物可以延长ADPKD患者的肾脏存活时间。我们的实验室通过高通量筛选确定了两类小分子CFTR抑制剂，噻唑烷酮和甘氨酸酰肼，在已发表的概念验证研究中，它们可有效预防ADPKD模型中的囊液蓄积。最近的一次大筛选产生了第三类嘧啶并吡咯并喹喔啉（PPQ）CFTR抑制剂，其具有独特的性质，在肾脏器官培养模型中预防囊肿扩张方面非常有效。本申请的第一个目的是使用肾器官培养和pkd 1敲除小鼠模型选择最佳的小分子CFTR抑制剂，用于预防ADPKD中的囊肿生长。将评价噻唑烷酮、甘氨酸酰肼和PPQ类CFTR抑制剂。这一目标的目标是选择每类有效防止囊肿生长、无毒和口服生物可利用的最佳抑制剂。第二个目标是根据药代动力学、ADME（吸收、分布、代谢、排泄）、毒性和致突变潜力的分析，优先选择第一个目标中选择的最佳CFTR抑制剂。目标是选择最好的一种或两种化合物用于进一步的临床前开发。 公共卫生相关性：多囊肾是最常见的遗传性疾病之一，也是导致肾衰竭需要透析或肾移植的主要原因。我们实验室发现的称为CFTR抑制剂的新候选药物将使用培养和动物模型测试其治疗多囊肾疾病的潜力。这种新的治疗形式可能最终延长多囊肾疾病的肾功能。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): Translational Science and specific Challenge Topic, 15- DK-103: Translate discovery of new molecules and pathways in pathogenesis of NIDDK diseases into potential therapies, diagnostics, or research tools. Polycystic kidney disease is one of the most common human genetic diseases and a major cause of chronic renal insufficiency requiring dialysis or kidney transplantation. There is compelling evidence that in autosomal dominant polycystic kidney disease (ADPKD) progressive fluid accumulation into cysts requires chloride secretion by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a cAMP-regulated chloride channel, which, when mutated, causes the genetic disease cystic fibrosis. Cyst growth in ADPKD requires fluid secretion into the cyst lumen coupled with epithelial cell hyperplasia. CFTR inhibitor 'antisecretory therapy' may offer life-long therapy to prolong kidney survival in ADPKD. At present there is no FDA-approved drug to prolong kidney survival in ADPKD. Our laboratory has identified, by high-throughput screening, two classes of small-molecule CFTR inhibitors, thiazolidinones and glycine hydrazides, which, in published proof-of-concept studies, are effective in preventing cyst fluid accumulation in ADPKD models. A large screen recently yielded a third class of pyrimido-pyrrolo-quinoxaline (PPQ) CFTR inhibitors that have unique properties and are very potent and effective in preventing cyst expansion in kidney organ culture models. The first aim of this application is to select, using kidney organ culture and pkd1 knockout mouse models, the best small-molecule CFTR inhibitors for preventing cyst growth in ADPKD. CFTR inhibitors of the thiazolidinone, glycine hydrazide and PPQ classes will be evaluated. The goal of this aim will be to select the best inhibitor(s) of each class that are effective in preventing cyst growth, non-toxic, and orally bioavailable. The second aim will be to prioritize the best CFTR inhibitors selected in the first aim, based on analyses of pharmacokinetics, ADME (absorption, distribution, metabolism, excretion), toxicity and mutagenic potential. The goal is to select the best one or two compounds for further pre-clinical development. PUBLIC HEALTH RELEVANCE: Polycystic kidney disease is one of the most common genetic diseases and a major cause of kidney failure leading to dialysis or kidney transplantation. New drug candidates, called CFTR inhibitors, discovered by our laboratory will be tested for their potential in treating polycystic kidney disease using culture and animal models. This new form of therapy might ultimately prolong kidney function in polycystic kidney disease.