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

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

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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.

项目摘要哮喘发病机理的特征是气道注射，重塑和反应性过高导致严重的支气管收缩。过敏原诱导的炎症介质对免疫细胞作用和结构气道细胞并激活细胞内信号传导。激活蛋白-1（AP-1）转录因子复合物是一种中央调节剂，对信号通路响应气道细胞中的细胞因子，生长因子和其他炎症信号介导气道重塑哮喘。因此，更新的AP-1有助于哮喘发病机理的多种特征，是一个有吸引力的抗哮喘治疗靶标。细胞外信号调节的蛋白激酶（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，我们确定了一种与唯一ERK1/2结合的新型化合物介导与AP-1复合蛋白相互作用并抑制ERK1/2-的相互作用的底物对接位点介导的AP-1活性。靶向选择激酶功能可在减少获得药物方面具有优势靶向ATP结合位点的当前激酶抑制剂观察到的抗性和毒性所有酶活性。我们证明功能选择性ERK1/2抑制剂抑制ASM细胞在鼠模型中，增殖，AP-1活性和减轻过敏性哮喘的多种特征。考虑到更新的ERK1/2活动有助于哮喘的发病机理，我们假设通过AP-1对ERK1/2信号传导的功能选择性抑制作用将减轻ASM和LF单元增生，肥大，细胞外基质（ECM）过度分泌以及哮喘的其他特征。这 R61阶段将由两个目标组成。 AIM 1将使用计算机辅助药物设计和化学合成为了生成铅功能选择性ERK1/2抑制剂的优化类似物，该抑制剂针对AP-的调节 1个蛋白质。 AIM 2将评估新化合物，以确定AP-1介导的增生，ECM分泌，从正常和哮喘肺中获得的原发性ASM和LF细胞中的炎症介质。目的 3在R33阶段将雇用哮喘的综合小鼠模型来评估最有效的减轻过敏性哮喘的多种特征的化合物。此外，R33阶段将与加速器合作伙伴Gen1E，生命科学，以进行临床前测试和开发顶部 3种侧重于药代动力学评估，激酶选择性，脱靶效应和毒性的化合物。这些研究将提供重要的临床前数据，以进步有效抑制的新型疗法参与哮喘病理学的主要效应靶标（例如AP-1）。