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Evaluation of novel substrate specific inhibitors of ERK1/2 in the treatment of asthma

新型ERK1/2底物特异性抑制剂治疗哮喘的评价

基本信息

批准号：
9174204
负责人：
Deepak A Deshpande
金额：
$ 24.61万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-10 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174204
关键词：
Address Affect Allergens Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Arthritis Asthma Atherosclerosis Binding Binding Sites Breathing Bronchoconstriction Carcinogens Catalytic Domain Cell Count Cell Cycle Progression Cell Proliferation Cell Size Cell Survival Cell secretion Cells Chemicals Chronic Disease Chronic Obstructive Airway Disease Clinical Data Clinical Trials Complex Computer Assisted Data Development Disease Disease Progression Down-Regulation Drug Design Drug Targeting Drug resistance Drug toxicity EGF gene Effectiveness Epithelial Cells Evaluation Extracellular Matrix FOS gene Family Fibrosis Gene Expression Growth Health Care Costs Hepatitis Human Hyperplasia Immune Inflammation Inflammation Mediators Inflammatory Interleukin-13 Interleukin-4 Interleukin-5 Lead Lung MAPK11 gene MAPK3 gene MAPK8 gene Malignant Neoplasms Mediating Mediator of activation protein Methods Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Morbidity - disease rate Mucous body substance Normal Cell Parkinson Disease Pathogenesis Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Platelet-Derived Growth Factor Production Protein Family Proteins Psoriasis Pyroglyphidae Regulation Role Safety Severity of illness Signal Pathway Signal Transduction Signaling Molecule Site Smooth Muscle Myocytes Specificity Stimulus Testing Therapeutic Intervention Time Tissues Toxic effect Transcription Factor AP-1 Transcriptional Activation Up-Regulation Validation airway hyperresponsiveness airway inflammation airway remodeling angiogenesis asthmatic cell growth cell type chemokine cytokine in vivo inhibitor/antagonist kinase inhibitor mortality mouse model novel novel strategies pre-clinical protein function receptor respiratory smooth muscle response scaffold small molecule inhibitor success therapeutic target transcription factor validation studies

项目摘要

PROJECT SUMMARY: Airway inflammatory diseases, such as asthma, are characterized by inflammation, airway remodeling and hyperresponsiveness resulting in severe bronchoconstriction. Asthma pathogenesis is driven by inflammatory mediators that act on immune cells and resident airways cells through receptors that regulate signaling molecules and gene expression. Transcriptional activation is a common end point in the signaling elicited by multiple cytokines in target cells. The transcription factor, Activator Protein (AP)-1 is activated by mitogen-activated protein (MAP) kinases, such as ERK1/2, and is known to mediate airway inflammation, airway smooth muscle (ASM) remodeling, and mucus production, and therefore is an attractive anti-asthma therapeutic target. Current kinase inhibitors used as anti-inflammatory or anti-oncogenic agents target ATP binding or catalytic sites and block all enzymatic activity. These drugs invariably lead to drug resistance or toxicity due to lack of specificity. Using advanced computer-aided drug design methods we have identified a novel thienyl benzenesulfonate chemical scaffold that selectively inhibits ERK1/2-mediated AP-1 activity taking advantage of the structural requirements of ERK1/2 and specific substrates. These novel substrate- specific inhibitors of ERK1/2 bind the F-recruitment site (FRS) of ERK1/2, which mediates interactions with AP-1 substrates containing an F-site or FXF motif. Functional validation studies demonstrate that the compounds inhibit specific kinase functions associated with disease while preserving ERK1/2 functions in normal cells. In this proposal we aim at evaluating the efficacy of newly developed small molecule inhibitors of ERK1/2 in mitigating features of asthma. Aim 1 studies will establish the effect of substrate-specific inhibitors of ERK1/2 on human ASM cell growth and secretion of extracellular matrix, chemokines and cytokines. Aim 2 studies will ascertain specificity and signaling mechanisms modulated by these compounds. Finally, we will employ an integrated mouse model of asthma to determine the in vivo efficacy of ERK1/2 inhibitors in mitigating allergen-induced airway inflammation, remodeling, mucus production and airway hyperresponsiveness. Preliminary data suggest that the compounds inhibit mitogen-induced ASM cell growth and AP-1 activation. Importantly, the compounds did not inhibit growth factor-induced phosphorylation of ERK1/2 or Akt further confirming the specificity of targeting downstream ERK1/2 substrates in ASM. Considering the ubiquitous expression and functional role of ERK1/2-induced activation of AP-1 in asthma pathogenesis, we predict that novel substrate specific inhibitors of ERK1/2 mitigate multiple features of asthma in the animal model. These studies will provide important pre-clinical data to advance a novel class of small molecule inhibitors targeting a versatile signaling molecule as anti-asthma therapies.

项目总结：呼吸道炎症性疾病，如哮喘，以炎症、呼吸道炎症为特征重塑和高反应性导致严重的支气管收缩。哮喘发病机制是由炎症介质驱动的，通过作用于免疫细胞和常驻呼吸道细胞调节信号分子和基因表达的受体。转录激活是一种靶细胞中多种细胞因子诱导的信号转导的共同终点。抄写激活蛋白(AP)-1由丝裂原活化蛋白(MAP)激酶激活，如 ERK1/2，并被认为是介导呼吸道炎症、气道平滑肌(ASM)重塑和粘液产生，因此是一个有吸引力的抗哮喘治疗靶点。电流激活酶用作抗炎或抗肿瘤药物的抑制剂靶向于ATP结合或催化部位和阻断所有的酶活性。这些药物总是由于缺乏药物而产生耐药性或毒性。专一性。利用先进的计算机辅助药物设计方法，我们鉴定了一种新的噻吩基选择性抑制ERK1/2介导的AP-1活性的苯磺酸化学支架 ERK1/2和特定衬底的结构要求的优势。这些新的衬底- ERK1/2的特异性抑制物结合ERK1/2的F-募集位点(FRs)，介导相互作用 AP-1底物含有F-位或FXF基序。功能验证研究表明这些化合物抑制与疾病相关的特定激酶功能，同时保留ERK1/2 在正常细胞中起作用。在这项建议中，我们旨在评估新开发的Small的疗效 ERK1/2分子抑制剂在缓解哮喘中的作用。目标1的研究将确定这种影响底物特异性ERK1/2抑制剂对人ASM细胞生长和胞外分泌的影响基质、趋化因子和细胞因子。AIM 2研究将确定特异性和信号机制受这些化合物的影响。最后，我们将使用哮喘的集成小鼠模型来确定ERK1/2抑制剂在减轻变应原诱导的呼吸道炎症中的体内疗效，重塑、粘液产生和呼吸道高反应性。初步数据显示，化合物抑制丝裂原诱导的ASM细胞生长和AP-1激活。重要的是，化合物不能抑制生长因子诱导的ERK1/2或Akt的磷酸化 ASM靶向ERK1/2下游底物的特异性。考虑到无所不在的 ERK1/2诱导AP-1活化在哮喘发病机制中的表达及功能作用预测新型底物特异性ERK1/2抑制剂缓解哮喘的多种特征动物模型。这些研究将提供重要的临床前数据，以推动一类新的小型以多功能信号分子为靶点的分子抑制剂作为抗哮喘疗法。