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)：翻译科学和特定挑战主题，15-DK-103：将NIDDK疾病发病机制中新分子和途径的发现转化为潜在的治疗、诊断或研究工具。多囊肾病是人类最常见的遗传病之一，也是慢性肾功能不全的主要原因，需要透析或肾移植。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，进行性的液体积聚到囊中需要囊性纤维化跨膜传导调节蛋白(CFTR)的氯离子分泌，CFTR是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中的囊性生长需要向囊腔内分泌液体，并伴有上皮细胞的增生。CFTR抑制剂“抗分泌疗法”可能为ADPKD患者提供终生治疗以延长肾脏存活期。目前尚无FDA批准的延长ADPKD患者肾脏存活的药物。我们的实验室已经通过高通量筛选确定了两类小分子CFTR抑制剂，噻唑烷酮类和甘氨酸肼，在已发表的概念验证研究中，它们可以有效地防止ADPKD模型中囊液的积聚。大屏幕最近产生了第三类嘧啶-吡咯喹恶啉(PPQ)CFTR抑制剂，具有独特的性质，在肾脏器官培养模型中非常有效和有效地防止囊性扩张。这项应用的第一个目的是利用肾脏器官培养和PKD1基因敲除小鼠模型，选择最好的小分子CFTR抑制剂来防止ADPKD的囊性生长。将对噻唑烷酮类、甘氨酸肼类和PPQ类CFTR抑制剂进行评估。这一目标的目标将是选择每一类最好的抑制剂(S)，它们有效地防止囊肿生长，无毒，口服生物利用度。第二个目标是根据药代动力学、ADME(吸收、分布、代谢、排泄)、毒性和诱变潜力的分析，优先选择第一个目标中选择的最佳CFTR抑制剂。其目标是为进一步的临床前开发选择最好的一到两种化合物。 公共卫生相关性：多囊肾病是最常见的遗传性疾病之一，也是导致肾功能衰竭导致透析或肾移植的主要原因。我们实验室发现的新的候选药物，称为CFTR抑制剂，将通过培养和动物模型来测试它们在治疗多囊肾病方面的潜力。这种新的治疗形式可能最终延长多囊肾病患者的肾功能。

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.