PHARMACOLOGICAL TARGETING OF GALPHA SUBUNITS IN DISEASE

疾病中 GALPHA 亚基的药理学靶向

基本信息

批准号：
10451720
负责人：
Kendall J Blumer
金额：
$ 46.06万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10451720
关键词：
Acute Address Alzheimer&apos s Disease Amino Acids Animal Disease Models Antibodies Basic Science Behavior Disorders Binding Binding Sites Biochemical Biological Assay Biophysical Process Biopsy Cardiovascular Diseases Cells Chemicals Chronic Clinical Clinical Research Clinical Trials Cyclodepsipeptides Diabetes Mellitus Disease Docking Dose-Limiting Drug Targeting Drug Tolerance Elements Family Foundations Funding G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits GTP-Binding Proteins Goals Growth Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Hemangioma Hepatic Heterotrimeric GTP-Binding Proteins Hormones Hypocalcemia Hypoparathyroidism Individual Inflammatory Knock-out Knowledge Lethal Dose 50 Lung diseases Malignant Neoplasms Mediating Melanoma Cell Modeling Mus Natural Products Neoplasms Obesity Oncogenic Organic Chemistry Patients Pharmacology Phase Physiological Physiology Pituitary Neoplasms Process Protein Inhibition Receptor Signaling Regulation Route S phase Side Solid Source Sturge-Weber Syndrome System Therapeutic Tissues Toxic effect Uveal Melanoma Work Xenograft procedure analog base biophysical analysis blood pressure reduction computerized tools cost design drug discovery druggable target effective therapy inhibitor innovation insight knock-down molecular dynamics mouse model mucosal melanoma mutant nanoparticle novel pre-clinical preclinical study protein function receptor respiratory side effect single-molecule FRET targeted delivery therapeutic development therapeutic lead compound therapeutically effective tumor

项目摘要

Project Summary/Abstract This multi-PI basic science project aims to transform understanding of G-protein function in physiology and disease, and provide broadly applicable routes for developing therapeutics to treat currently untreatable diseases caused by mutant constitutively active G protein α-subunits. It does so by developing knowledge required to design and synthesize, at scales required for preclinical and eventual clinical studies, a family of bioavailable inhibitors, each of which selectively targets closely related groups of heterotrimeric G proteins. The translational/clinical potential of this approach is based on recent studies indicating that a bioavailable inhibitor that targets G protein α-subunits of the Gq/11 class is therapeutically effective in mouse models of uveal melanoma, an untreatable disease that is driven by mutant constitutively active Gq/11. Similar approaches could have broad impact, because many other untreatable diseases are driven by various types of mutant constitutively active G protein α-subunits, including hormone-secreting pituitary tumors, mucosal melanoma, choroidal hemangiomas, hepatic small-vessel neoplasms, ~10-15% of all cancers, Sturge-Weber syndrome, autosomal dominant hypoparathyroidism, and certain forms of hyper- and hypocalcemia. Moreover, this approach could be used to modulate G-protein activity in diseases where GPCR-targeted drugs are ineffective due to receptor redundancy or to G proteins that cause dose-limiting side effects such as respiratory suppression or drug tolerance. Bioavailable inhibitors that directly target specific subclasses of G proteins would be extremely valuable for basic science. They would provide simple, fast, cheap and reliable chemical probes with which to identify novel functions of G proteins in normal physiology and in animal models of disease, in contrast to conventional knockout or knockdown strategies, which are slow and expensive, and can suffer from compensatory or off- target effects. The foundation of this project is a pair of nearly identical, bioavailable, cyclic depsipeptide natural products that potently and selectively inhibit the Gq/11 subfamily of G protein α-subunits. The Specific Aims of this project will address four crucial challenges: 1) limited availability of these inhibitors; 2) lack of inhibitor derivatives that could be targeted to disease tissues for chronic therapy; 3) limited understanding of the inhibitory mechanism, which has precluded design of inhibitors that target other subtypes of G proteins; and 4) absence of inhibitors that selectively target G protein subtypes other than Gq/11. These Aims will be pursued by using innovative synthetic organic chemistry, computational-based docking and inhibitor design, single- molecule FRET, NMR, and biochemical and cell-based assays of G protein function.

项目摘要/摘要这个多PI基本科学项目旨在改变对生理学中G蛋白功能的理解和疾病，并提供广泛适用的途径，用于开发治疗当前不可治疗的治疗由组成型活性G蛋白α-亚基引起的疾病。它通过发展知识来做到这一点在临床前和最终临床研究所需的尺度上设计和合成所需的可生物利用的抑制剂，每种抑制剂均选择性地靶向异三聚体G蛋白的紧密相关组。这种方法的翻译/临床潜力基于最近的研究，表明可生物利用靶向GQ/11类的G蛋白α-亚基的抑制剂在小鼠模型中有效卵子黑色素瘤，一种不可治疗的疾病，由突变体活性GQ/11驱动。相似的方法可能会产生广泛的影响，因为许多其他不可治疗的疾病是由各种类型的组成型活性G蛋白α-亚基蛋白的突变体，包括分泌马的肿瘤，粘膜黑色素瘤，脉络膜血管瘤，肝小血管肿瘤，所有癌症的10-15％，Sturge-weber 综合征，常染色体显性甲状腺功能减退症以及某些形式的高血钙和低钙血症。而且，这种方法可用于调节以GPCR为靶标的药物的疾病中的G蛋白活性由于受体的冗余或G蛋白引起的剂量限制副作用，例如呼吸抑制或药物耐受性。直接针对G蛋白特定子类的生物利用抑制剂将非常有价值用于基础科学。他们将提供简单，快速，便宜和可靠的化学问题来识别 G蛋白在正常生理学和疾病动物模型中的新功能与常规缓慢且昂贵的淘汰或敲除策略，可能会遭受补偿性或偏离目标效应。该项目的基础是一对几乎相同的，生物可用的，环状深度肽天然的潜在和选择性地抑制G蛋白α-亚基的GQ/11亚家族的产物。具体目的该项目将解决四个至关重要的挑战：1）这些抑制剂的可用性有限； 2）缺乏抑制剂可以针对疾病组织进行慢性治疗的衍生物； 3）对抑制机制，它排除了针对其他亚型G蛋白的抑制剂的设计；和4）除了GQ/11以外，没有选择性靶向G蛋白亚型的抑制剂。这些目标将被追求通过使用创新的合成有机化学，基于计算的对接和抑制剂设计，单个 G蛋白功能的分子FRET，NMR以及生化和基于细胞的测定。