Novel molecular therapeutics for cystic fibrosis

囊性纤维化的新型分子疗法

基本信息

批准号：
8782036
负责人：
David E Sterner
金额：
$ 66.84万
依托单位：
PROGENRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8782036
关键词：
Accounting Address American Animal Model Anti-Inflammatory Agents Antibiotics Area Bacteria Biochemical Biological Assay Biology Cell membrane Cell model Cell surface Cells Cellular Assay Cessation of life Chloride Ion Chlorides Chronic Disease Clinical Trials Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Degradation Pathway Development Disease Drug Kinetics Drug Targeting Effectiveness Endoplasmic Reticulum Enhancers Enzymes FDA approved Fingers Gastrointestinal tract structure Goals Growth Hereditary Disease In Vitro Individual Infection Lead Ligase Lung Measures Membrane Membrane Proteins Modeling Molecular Mucolytics Mucous body substance Mutate Mutation Pathology Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Phenylalanine Plant Roots Positioning Attribute Progress Reports Property Proteins Recurrence Regulation Salts Sodium Chloride Symptoms Testing Therapeutic Therapeutic Agents Therapeutic Effect Ubiquitin Uncertainty Up-Regulation VX-770 VX-809 Validation base cystic fibrosis patients disability drug candidate drug discovery drug metabolism high throughput screening improved in vitro activity in vivo inhibitor/antagonist interest meetings member microorganism multicatalytic endopeptidase complex mutant novel pre-clinical protein degradation public health relevance small molecule trafficking ubiquitin-protein ligase

项目摘要

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.

描述（由适用提供）：囊性纤维化（CF）导致慢性疾病，残疾和早期死亡。由于细菌和绝对粘性粘液中细菌和其他微生物的生长，复发性肺部感染是致命的。抗生素，粘液溶剂和抗炎剂仅对处理某些CF效应有用。然而，最近，FDA批准了解决CF根本原因的Ivacaftor（又称VX-770或Kalydeco）。不幸的是，它在大多数患者中无效。 CF的根本原因是囊性纤维化跨膜电导调节剂（CFTR）的突变，通常将其定位于细胞膜并控制盐水平。在CF中，突变降低了CFTR的数量或活性，并且所得的盐失调导致CF病理。主要突变（在美国> 90％，在全球范围内约75％）是F508，是CFTR中单个苯丙氨酸居住地的缺失。 F508导致CFTR折叠不当，其中大多数在内质网中降解，并且没有到达细胞膜。如果可以将其定位在膜上，并且正在开发“校正”药物（例如VX-809/LumAcaftor），则正在开发CFTR¿F508，以促进将突变体CFTR促进到细胞表面的运输。通过介入调节蛋白质（包括泛素/蛋白酶体途径）的各种细胞途径，增加了CFTR¿F508的水平，运输和/或功能的其他方法。错误折叠的cftr¿f508被泛素E3连接酶GP78泛素化，并通过ERAD（内质网相关蛋白质降解）降解，从而降低了其细胞水平。 GP78的敲低导致细胞中CFTR¿F508的水平急剧增加，并增加了氯化物的转运。 GP78的抑制作用应增加细胞表面的CFTR量，并且可以单独使用或与校正器（例如VX-809）相结合。在第一阶段，确定了GP78的小分子抑制剂，并表明，通过细胞测定法判断，它们增加功能CFTR的水平。这些命中之一（GP1）提高了核心糖基化的CFTR¿F508的水平，并且与VX-809结合使用时，增加了细胞中功能CFTRTO的功能CFTRTO水平，从而进一步验证了GP78作为治疗CF的靶标。在第二阶段，GP1和其他HIT化合物将通过药物化学优化，通过体外和基于细胞的次要测定进行分析，并在动物模型中进行了测试，用于药物代谢/药代动力学特性，目的是确定潜在的和选择性的铅化合物，并具有有效性的囊肿纤维化药物。