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IRE1beta Inhibitors: Novel Therapeutics to Manage Excess Mucus in Asthma

IRE1beta 抑制剂：治疗哮喘过多粘液的新疗法

基本信息

批准号：
9918873
负责人：
Emily Arthur Hull-Ryde
金额：
$ 30万
依托单位：
IREX PHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-19 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918873
关键词：
Adrenal Cortex Hormones Adult American Amino Acids Anabolism Anti-Cholinergics Anti-Inflammatory Agents Asthma Binding Biochemical Biological Biological Assay Cell Culture Techniques Cell Death Cells Cessation of life Chemistry Childhood Clinic Data Development Economic Burden Endoplasmic Reticulum Enzymes Evaluation Exhibits Exposure to Gastrointestinal tract structure Goals Hospital Costs Human Inhalation Therapy Inositol Institutes Interleukin-13 Isoenzymes Knowledge Lead Ligand Binding Ligands Link Lung MUC5AC gene Mammals Mediating Medical Modeling Molecular Conformation Morbidity - disease rate Mucins Mucolytics Mucous body substance Mus North Carolina Obstruction Pharmaceutical Chemistry Phase Phosphotransferases Physicians Production Productivity Protein Isoforms Proteins Pulmonology Pyroglyphidae Respiratory System Respiratory physiology Ribonucleases Scientist Small Business Technology Transfer Research Stimulus Structure Structure-Activity Relationship Synthesis Chemistry Testing Therapeutic Toxic effect Universities airway epithelium airway hyperresponsiveness airway inflammation analog asthma exacerbation asthmatic asthmatic airway asthmatic patient base bronchial epithelium commercialization computational chemistry cytokine cytotoxicity design endoplasmic reticulum stress in vivo inhibitor/antagonist innovation kinase inhibitor meetings mortality nanomolar novel novel therapeutics sensor side effect small molecule small molecule inhibitor

项目摘要

PROJECT SUMMARY Over 25 million Americans have asthma, which places an economic burden on the U.S. of $81.9 billion. Airway mucus overproduction is a hallmark of asthma, and the quantity and tenacity of mucus are increased during airway exacerbations. Mucolytics degrade mucus, but do not reduce its production. Although corticosteroids and other anti-inflammatory therapies indirectly decrease mucus production, and anti-cholinergics inhibit mucus release from airway epithelia, a significant number of asthmatic continue to suffer from asthma exacerbations. Clear unmet medical need exists for new therapeutics that directly target airway mucus overproduction. Airway inflammation and excess mucins activate inositol requiring enzyme 1 (IRE1), a transmembrane endoplasmic reticulum protein that contains cytoplasmic kinase and RNase domains. IRE1 exists in two isoforms, α and β. IRE1α is ubiquitously expressed, but IRE1β is only expressed in mucous cells of the respiratory and GI tracts. Key residues in the kinase ligand binding pocket differ for the two isozymes. Activation of IRE1β (but not IRE1α) kinase and RNase is required for airway mucin production. IRE1β (but not IRE1α) expression is up-regulated in asthmatic human bronchial epithelia (HBE), providing an amplifying mechanism for airway exacerbations due to mucus overproduction. Irex Pharma has developed novel IRE1β- specific assays to support a full synthetic medicinal chemistry campaign to identify potent, selective and efficacious IRE1β inhibitors to treat airway mucus overproduction. Our focused testing of IRE1 ligands revealed a distinct mechanism for blocking IRE1β-dependent mucin production. Most IRE1 kinase inhibitors tested activate the IRE1 RNase. We identified an IRE1β ligand that blocks both kinase and RNase activities and mucin production in HBE, providing proof-of-concept that a small molecule IRE1β ligand with this profile can block mucus overproduction in human airways. Aim 1 proposes to use structure-based design to guide the synthesis of novel analogs based on our current hits. Structure-activity relationships will be established using an iterative approach. Our goal is to identify nontoxic, patentable, nanomolar compound(s) using our team's extensive knowledge of kinase inhibitor design, computational chemistry, synthetic chemistry, and novel IRE1 assays. Aim 2 proposes to test our IRE1β inhibitors with favorable profiles for ability to reduce 1) interleukin-13 (IL-13)-stimulated MUC5AC production in HBE cultures and 2) house dust mite (HDM; an in vivo stimulus relevant to asthma)-induced airway mucin overproduction and hyper-responsiveness in mice. PK, early ADMET and kinase selectivity will be obtained for top compounds. Our goal is to identify a patentable IRE1β inhibitor able to reduce IL-13-increased MUC5AC in HBE and able to lower HDM-induced MUC5AC production and hyper-responsiveness in mouse airways with favorable potency, selectivity, toxicity and developability profiles. Completion of these studies will lay the groundwork for Phase II development of IRE1β antagonists as novel therapeutics for asthma.

项目摘要超过2500万美国人患有哮喘，给美国带来了819亿美元的经济负担。气道粘液过度产生是哮喘的一个标志，在哮喘发作期间，粘液的数量和韧性增加。气道恶化。粘液溶解剂降解粘液，但不减少其产生。虽然皮质类固醇和其他抗炎疗法间接减少粘液产生，抗胆碱能药物抑制气道上皮细胞释放粘液，相当数量的哮喘患者继续患有哮喘加重对于直接靶向气道粘液的新疗法存在明确的未满足的医疗需求生产过剩。气道炎症和过量粘蛋白激活肌醇需要酶1（IRE 1），一种跨膜内质网蛋白，含有胞质激酶和核糖核酸酶结构域。IRE1 存在两种异构体，α和β。IRE 1 α广泛表达，而IRE 1 β仅在粘液细胞中表达呼吸道和胃肠道的感染激酶配体结合口袋中的关键残基对于两种同工酶不同。气道粘蛋白的产生需要IRE 1 β（而不是IRE 1 α）激酶和RNA酶的活化。IRE 1 β（但不是 IRE 1 α）在哮喘人支气管上皮细胞（HBE）中表达上调，为哮喘的发生提供了一个放大的证据。由于粘液过度产生导致的气道恶化的机制。Irex Pharma开发了新型IRE 1 β- 支持全面合成药物化学活动的特定测定，以鉴定强效、选择性和有效的IRE 1 β抑制剂治疗气道粘液过度产生。我们对IRE 1配体的重点检测揭示了阻断IRE 1 β依赖性粘蛋白产生的独特机制。大多数IRE 1激酶抑制剂测试激活IRE 1 RNase。我们鉴定了一种IRE 1 β配体，它可以阻断激酶和RNA酶的活性和粘蛋白的产生，提供了具有这种特征的小分子IRE 1 β配体可以阻止人体气道中粘液的过度分泌。目标1建议使用基于结构的设计来指导基于我们目前的热门产品合成新的类似物。将使用以下方法建立结构-活性关系迭代方法。我们的目标是利用我们团队的技术，激酶抑制剂设计，计算化学，合成化学和新型IRE 1的广泛知识分析。目的2提出测试我们的IRE 1 β抑制剂具有有利的降低1）白细胞介素-13的能力 HBE培养物中IL-13刺激的MUC 5AC产生和2）屋尘螨（HDM;体内刺激与哮喘相关）诱导的小鼠气道粘蛋白过度产生和高反应性。PK，早 ADMET和激酶的选择性将获得顶级化合物。我们的目标是确定一个可申请专利的IRE 1 β 能够降低HBE中IL-13增加MUC 5AC并能够降低HDM诱导的MUC 5AC产生的抑制剂在小鼠气道中具有良好的效力、选择性、毒性和可发展性数据区.这些研究的完成将为IRE 1 β拮抗剂的II期开发奠定基础，哮喘的新疗法。