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Optimizing function-selective ERK1/2 inhibitors for reducing AP-1-mediated airway pathology in asthma.

优化功能选择性 ERK1/2 抑制剂以减少 AP-1 介导的哮喘气道病理。

基本信息

批准号：
10666887
负责人：
Deepak A Deshpande
金额：
$ 52.5万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666887
关键词：
Allergens Anti-Asthmatic Agents Asthma Binding Binding Sites Biological Availability Biological Sciences Bronchoconstriction Cardiotoxicity Cell Line Cell Proliferation Cell physiology Cells Chemicals Chronic Collaborations Complex Computer Assisted Cysteine Data Disease Progression Docking Drug Design Drug Kinetics Drug Targeting Drug resistance Drug toxicity Enzymes Evaluation Extracellular Matrix Extracellular Signal Regulated Kinases Extrinsic asthma Family Fibroblasts Genetic Transcription Growth Factor Heterogeneity Human Hyperplasia Hypertrophy Immune Immunologics In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intravenous Lead Ligands Lung MAPK1 gene MAPK3 gene MAPK7 gene MAPK8 gene Mass Spectrum Analysis Mediating Mediator Methods Mitogen-Activated Protein Kinases Morbidity - disease rate Mus Normal Cell Obstructive Lung Diseases Oral PDGF inhibition Pathogenesis Pathologic Pathology Persons Pharmaceutical Preparations Pharmacology and Toxicology Phase Phosphotransferases Preclinical Testing Proliferating Property Protein Kinase Proteins Pyroglyphidae Quality of life Regulation STAT protein Scanning Severity of illness Signal Pathway Signal Transduction Signaling Molecule Site Slice Smooth Muscle Myocytes Solubility Structure Surface Plasmon Resonance Technology Testing Therapeutic Therapeutic Agents Tissues Toxic effect Toxicology Transcription Factor AP-1 Western Blotting acquired drug resistance adduct airway hyperresponsiveness airway inflammation airway remodeling analog asthma model asthmatic cell type chemical synthesis cytokine design efficacy evaluation extracellular improved in vivo in vivo Model inhibitor innovation kinase inhibitor mouse model novel novel therapeutics p38 Mitogen Activated Protein Kinase pharmacologic pre-clinical preclinical development preclinical study prevent protein complex pulmonary function rational design respiratory smooth muscle scaffold therapeutic target transcription factor

项目摘要

Project Summary Asthma pathogenesis is characterized by airway inflammation, remodeling and hyperresponsiveness resulting in severe bronchoconstriction. Allergen-induced inflammatory mediators act on immune cells and structural airways cells and activate intracellular signaling. The Activator Protein-1 (AP-1) transcription factor complex is a central regulator that responds to signaling pathways activated by cytokines, growth factors and other inflammatory signals in airway cells to mediate airway remodeling in asthma. Therefore, upregulated AP-1, which contributes to multiple features of asthma pathogenesis, is an attractive anti-asthma therapeutic target. The Extracellular signal‑Regulated protein Kinases (ERK1/2) are key regulators of AP-1 activity in airway smooth muscle (ASM), lung fibroblasts (LF), and other lung cells that contribute to the pathology of asthma. Taking advantage of ERK1/2 structural interactions with specific substrates, we identified a novel compound that binds to a unique ERK1/2 substrate docking site that mediates interactions with AP-1 complex proteins and inhibits ERK1/2- mediated AP-1 activity. Targeting select kinase functions offers advantages in reducing acquired drug resistance and toxicity observed with the current kinase inhibitors that target ATP binding sites and block all enzymatic activity. We demonstrate that function-selective ERK1/2 inhibitors inhibit ASM cell proliferation, AP-1 activity, and mitigate multiple features of allergic asthma in a murine model. Considering that upregulated ERK1/2 activity contributes to the pathogenesis of asthma, we hypothesize that function-selective inhibition of ERK1/2 signaling through the AP-1 will mitigate ASM and LF cell hyperplasia, hypertrophy, extracellular matrix (ECM) hypersecretion, and other features of asthma. The R61 phase will consist of two aims. Aim 1 will use computer-aided drug design and chemical synthesis to generate optimized analogs of a lead function-selective ERK1/2 inhibitor that targets regulation of AP- 1 proteins. Aim 2 will evaluate new compounds in regulating AP-1 mediated hyperplasia, ECM secretion, and inflammatory mediators in primary ASM and LF cells obtained from normal and asthmatic lungs. Aim 3 in the R33 phase will employ an integrated mouse model of asthma to assess the most potent compounds in mitigating multiple features of allergic asthma. In addition, R33 phase will collaborate with an Accelerator Partner, Gen1E, Life Sciences, to perform pre-clinical testing and development of the top 3 compounds focusing on pharmacokinetic evaluation, kinase selectivity, off-target effects, and toxicity. These studies will provide important pre-clinical data to advance a novel therapy that effectively inhibits a major effector target (e.g., AP-1) involved in the pathology of asthma.

项目摘要哮喘的发病机制以气道炎症、重塑和高反应性为特征导致严重的支气管收缩。过敏原诱导的炎症介质作用于免疫细胞和结构气道细胞并激活细胞内信号。激活蛋白-1（AP-1）转录因子复合物是一个中央调节器，响应信号通路激活，细胞因子、生长因子和其他炎症信号介导气道重塑。哮喘因此，导致哮喘发病机制多种特征的AP-1上调，一个有吸引力的抗哮喘治疗靶点。细胞外信号调节蛋白激酶 (ERK1/2）是气道平滑肌（ASM）、肺成纤维细胞（LF）和导致哮喘病理的其他肺细胞。利用ERK1/2结构与特定底物的相互作用，我们确定了一种新的化合物，结合到独特的ERK 1/2 介导与AP-1复合物蛋白相互作用并抑制ERK 1/2的底物对接位点。介导的AP-1活性。靶向选择激酶功能提供了减少获得性药物目前的激酶抑制剂靶向ATP结合位点，所有的酶活性。我们证明了功能选择性ERK 1/2抑制剂抑制ASM细胞，增殖、AP-1活性，并减轻小鼠模型中过敏性哮喘的多种特征。考虑到ERK 1/2活性的上调参与了哮喘的发病机制，我们假设：通过AP-1功能选择性抑制ERK1/2信号传导将减轻ASM和LF细胞增生、肥大、细胞外基质（ECM）分泌过多和哮喘的其他特征。的 R61阶段将包括两个目标。AIM1将使用计算机辅助药物设计和化学合成以产生靶向AP-1调节的先导功能选择性ERK 1/2抑制剂的优化类似物， 1蛋白质。目的2：评价新化合物在AP-1介导的细胞增殖、ECM分泌、以及从正常和哮喘肺获得的原代ASM和LF细胞中的炎症介质。目的 3在R33阶段将采用哮喘的综合小鼠模型来评估最有效的化合物在缓解过敏性哮喘的多种特征中的作用。此外，R33阶段将与加速器合作伙伴Gen1E，生命科学，执行临床前测试和开发顶级 3种化合物，侧重于药代动力学评价、激酶选择性、脱靶效应和毒性。这些研究将提供重要的临床前数据，以推进一种新的治疗方法，主要效应靶（例如，AP-1）参与哮喘的病理过程。