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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：
9293245
负责人：
Deepak A Deshpande
金额：
$ 19.41万
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 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293245
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 Extracellular Signal Regulated Kinases FOS Protein FOS gene FOXP3 gene Family Fibrosis Fos-Related Antigens Gene Expression Growth Growth Factor Health Care Costs Hepatitis Human Hyperplasia Immune Inflammation Inflammation Mediators Inflammatory Interleukin-13 Interleukin-4 Interleukin-5 Lead Lung MAPK14 gene MAPK8 gene Malignant Neoplasms Mediating Mediator of activation protein Methods Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Morbidity - disease rate Mucous body substance Muscle Cells Normal Cell Parkinson Disease Pathogenesis Pathologic Pharmaceutical Preparations Pharmacology Phenotype Phosphorylation Phosphotransferases Platelet-Derived Growth Factor Production Proteins Psoriasis Pyroglyphidae Recruitment Activity 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 Validation activator 1 protein 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 targeted agent 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.

项目概要：气道炎性疾病，如哮喘，其特征在于炎症，气道炎症，重塑和高反应性导致严重的支气管收缩。哮喘发病由炎症介质驱动，炎症介质通过以下方式作用于免疫细胞和常驻气道细胞：调节信号分子和基因表达的受体。转录激活是一种在靶细胞中由多种细胞因子引起的信号传导中的共同终点。转录激活蛋白（AP）-1因子被促分裂原激活蛋白（MAP）激酶激活，如 ERK 1/2，并且已知介导气道炎症、气道平滑肌（ASM）重塑和粘液产生，因此是有吸引力的抗哮喘治疗靶点。电流激酶用作抗炎或抗癌剂的抑制剂靶向ATP结合或催化位点，阻止所有酶活性。这些药物总是由于缺乏抗病毒药物而导致耐药性或毒性。的特异性利用先进的计算机辅助药物设计方法，我们已经确定了一个新的噻吩选择性抑制ERK 1/2介导的AP-1活性摄取的苯磺酸盐化学支架 ERK 1/2和特定底物的结构要求的优势。这些新的基质- ERK 1/2的特异性抑制剂结合ERK 1/2的F-募集位点（FRS），其介导相互作用与含有F-位点或FXF基序的AP-1底物反应。功能验证研究表明，该化合物抑制与疾病相关的特异性激酶功能，同时保留ERK 1/2，在正常细胞中发挥作用。在这项建议中，我们的目的是评估新开发的小剂量 ERK 1/2分子抑制剂在缓解哮喘中的作用。目标1研究将确定效果 ERK 1/2底物特异性抑制剂对人ASM细胞生长和细胞外基质、趋化因子和细胞因子。目的2研究将确定特异性和信号机制由这些化合物调节。最后，我们将采用一个完整的哮喘小鼠模型，确定ERK 1/2抑制剂在减轻过敏原诱导的气道炎症中的体内功效，重塑、粘液产生和气道高反应性。初步数据显示，化合物抑制有丝分裂原诱导的ASM细胞生长和AP-1激活。重要的是化合物不抑制生长因子诱导的ERK 1/2或Akt磷酸化，进一步证实了 ASM中靶向下游ERK 1/2底物的特异性。考虑到无处不在的研究ERK 1/2诱导的AP-1活化在哮喘发病机制中的作用，预测新型ERK 1/2底物特异性抑制剂可减轻哮喘的多种特征，动物模型这些研究将提供重要的临床前数据，以推进一类新的小分子药物。靶向多功能信号分子的分子抑制剂作为抗哮喘疗法。