Novel molecular therapeutics for cystic fibrosis

描述（由申请人提供）：囊性纤维化（CF）导致慢性疾病，残疾和早期死亡。由于细菌和其他微生物在异常粘稠的粘液中生长，复发性肺部感染是致命的。抗生素、粘液溶解剂和抗炎剂仅用于治疗某些CF效应。然而，最近，ivacaftor（a.k.a. VX-770或Kalydeco），它解决了CF的根本原因，被FDA批准。不幸的是，它对大多数患者无效。CF的根本原因是囊性纤维化跨膜传导调节因子（CFTR）的突变，该调节因子通常定位于细胞膜并控制盐水平。在CF中，突变降低CFTR的量或活性，并且所得的盐失调导致CF病理。主要突变（在美国> 90%，全球约75%）是<$F508，CFTR中单个苯丙氨酸残基的缺失。F508导致CFTR的不正确折叠，其中大部分在内质网（ER）中降解，并且不能到达细胞膜。CFTR如果F508可以定位于细胞膜，则它是部分功能性的，并且正在开发诸如VX-809/Lumacaftor的“校正剂”药物以促进突变CFTR向细胞表面的运输。增加CFTR？F508的水平、运输和/或功能的其他方法正在通过干预调节蛋白质的各种细胞途径（包括泛素/蛋白酶体途径）来寻求。错误折叠的CFTR ¶ F508被泛素E3连接酶gp 78泛素化，并通过ERAD（内质网相关蛋白降解）降解，降低其细胞水平。gp 78的敲低导致细胞中CFTR？F508水平显著增加，并增加氯离子转运。因此，gp 78抑制应该增加细胞表面CFTR的量，并且可以单独使用或与校正剂如VX-809组合使用。在I期，鉴定了gp 78的小分子抑制剂，并证明了它们增加功能性CFTR水平的能力，如通过细胞测定所判断的。这些命中之一（GP 1）增加了核心糖基化CFTR <$F508的水平，并且当与VX-809组合时，增加了细胞中功能性CFTR <$F508的水平，进一步验证了gp 78作为治疗CF的靶标。在第二阶段，GP 1和其他命中化合物将通过药物化学优化进行改进，通过体外和基于细胞的二次试验进行分析，并在动物模型中测试药物代谢/药代动力学特性，目的是确定有效和选择性的先导化合物作为囊性纤维化的治疗药物。

DESCRIPTION (provided by applicant): Cystic fibrosis (CF) leads to chronic illness, disability, and early death. Recurrent pulmonary infections are lethal owing to growth of bacteria and other microorganisms in the abnormally viscous mucus. Antibiotics, mucolytics, and anti-inflammatory agents, are useful only in treating some CF effects. Recently, however, ivacaftor (a.k.a. VX-770 or Kalydeco), which addresses the underlying cause of CF, was approved by the FDA. Unfortunately, it is ineffective in a majority of patients. The underlying cause of CF is a mutatio of the cystic fibrosis transmembrane conductance regulator (CFTR), which normally localizes to the cell membrane and controls salt levels. In CF, a mutation decreases the amount or activity of CFTR, and the resultant salt dysregulation leads to CF pathologies. The primary mutation (> 90% in the US and ~75% worldwide) is ¿F508, deletion of a single phenylalanine residue in CFTR. ¿F508 causes improper folding of CFTR, most of which is degraded in the endoplasmic reticulum (ER) and does not reach the cell membrane. CFTR¿F508 is partially functional if it can be localized to the membrane, and "corrector" drugs such as VX-809/lumacaftor are being developed to promote trafficking of mutant CFTR to the cell surface. Additional ways of increasing the levels, trafficking, and/or functionality of CFTR¿F508 are being sought by intervening in various cellular pathways that regulate proteins, including the ubiquitin/proteasome pathway. Misfolded CFTR¿F508 is ubiquitylated by the ubiquitin E3 ligase gp78 and degraded via ERAD (endoplasmic reticulum associated protein degradation), decreasing its cellular level. Knockdown of gp78 leads to dramatically increased levels of CFTR¿F508 in cells and increases chloride transport. Thus gp78 inhibition should increase the amount of CFTR at the cell surface and may be useful alone or combined with correctors such as VX-809. In phase I, small molecule inhibitors of gp78 were identified and their ability to increase levels of functional CFTR, as judged by cellular assays, demonstrated. One of these hits (GP1) increased the level of core glycosylated CFTR¿F508 and, when combined with VX-809, increased the level of functional CFTR¿F508 in cells, providing further validation of gp78 as a target for the treatment of CF. In Phase II, GP1 and additional hit compounds will be improved by medicinal chemistry optimization, analyzed by in vitro and cell-based secondary assays, and tested in animal models for drug metabolism/pharmacokinetic properties, with the goal of identifying potent and selective lead compounds with efficacy as therapeutic agents for cystic fibrosis.