Mitigation of Exaggerated Smooth Muscle Force with Inhibitors of Integrin Alpha2Beta1

使用整合素 Alpha2Beta1 抑制剂缓解过度的平滑肌力

基本信息

批准号：
10448088
负责人：
Hyunil Jo
金额：
$ 56.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-26 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448088
关键词：
Actins Acute Adhesions Adrenal Cortex Hormones Adrenergic beta-Agonists Animal Model Anti-Inflammatory Agents Antibodies Asthma Award Biological Assay Biological Availability Biology Bronchodilator Agents Calcium California Cells Characteristics Collagen Cryoelectron Microscopy Data Development Diagnosis Disease model Drug Design Drug Kinetics Extracellular Matrix Generations Goals Half-Life Homeostasis IgE Impairment In Vitro Inhalation Integrin alpha2beta1 Integrin alpha5beta1 Integrins Interleukin-13 Lead Leukotrienes Ligands Ligation Mediating Mediator of activation protein Medical Medicine Modification Mus Muscle Muscle Contraction Myosin ATPase Myosin Light Chain Kinase Nature Oral Parents Pathway interactions Patients Permeability Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Plasma Play Preclinical Drug Development Prodrugs Protein Inhibition Proteins Publishing Relaxation Research Proposals Role San Francisco Scientist Seasons Signal Transduction Smooth Muscle Smooth Muscle Myocytes Solubility Stimulus Structure Testing Therapeutic Therapeutic Uses Toxic effect Toxicology Universities Validation Work airway hyperresponsiveness allergic airway disease analog asthma model base candidate validation chronic respiratory disease cytokine design efficacy validation experience human tissue improved in vivo in vivo Model in vivo evaluation inhibitor lead optimization lead series methacholine novel novel strategies persistent symptom pharmacokinetics and pharmacodynamics professor protective effect respiratory smooth muscle scale up screening small molecule inhibitor targeted treatment therapeutic candidate tool transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT This is a new submission for an R61/R33 award for Dr. Aparna Sundaram (Assistant Professor, Department of Medicine) and Dr. Hyunil Jo (Assistant Professor, Department of Pharmaceutical Chemistry) at the University of California, San Francisco (UCSF). The long-term objectives of this proposal are to develop novel small molecule inhibitors of integrin α2β1 to disrupt force transmission in airway smooth muscle in chronic airways diseases such as asthma. Recent data published by Drs. Sundaram and Jo have shown that targeting proteins involved in smooth muscle tethering can impair force transmission in asthma models. Inhibition of these proteins result in protection against the exaggerated contraction induced by asthmagenic cytokines such as IL-13 ex vivo, or airway hyperresponsiveness in allergic airways disease models in vivo. Drs. Sundaram and Jo have shown that these protective effects occur independently of changes in intracellular actin-myosin crossbridging by directly modulating the tethering of smooth muscle to the surrounding matrix, suggesting that they can be combined with currently available bronchodilators acting on smooth muscle to further enhance relaxation. In this proposal Drs. Sundaram and Jo present preliminary data underscoring the importance of the smooth muscle tethering protein, integrin α2β1; ligation of this integrin results in protection against IL-13 enhanced contraction ex vivo and airway hyperresponsiveness in vivo. They have further shown proof of principle with the parent compound c15, and have made significant improvements in potency with A2-85, and even further optimization for oral delivery with compounds identified in this proposal. The R61 phase of this proposal seeks to synthesize and screen potent and specific small molecule inhibitors of integrin α2β1 with a structure-based-drug-design approach (Aim 1). Compounds will be further narrowed with in vitro optimization and ex vivo validation (Aim 2). Finally, hit compounds will be selected based on pharmacokinetic/pharmacodynamic studies to optimize oral delivery and in vivo testing in relevant disease models (Aim 3). The R33 phase of this proposal will further focus on lead series optimization. This proposal combines the efforts of two scientists with expertise in smooth muscle biology and de novo drug design who have already successfully collaborated together on the design and development of novel integrin inhibitors, along with a seasoned team of collaborators and consultants with experience in pre-clinical drug development. Accordingly, the R61 phase of this proposal aims to provide a lead series and the subsequent R33 phase will further focus on selection of a developmental candidate for therapeutic use in poorly controlled asthma.

项目概要/摘要这是 Aparna Sundaram 博士（助理教授，医学系）和 Hyunil Jo 博士（药物化学系助理教授）加州大学旧金山分校 (UCSF) 该提案的长期目标是发展。新型整合素α2β1小分子抑制剂可破坏气道平滑肌的力传递慢性气道疾病，例如哮喘。 Sundaram 和 Jo 博士最近发表的数据表明，靶向参与平滑肌的蛋白质。肌肉束缚会损害哮喘模型中的力传递，抑制这些蛋白质会导致。防止由哮喘细胞因子（例如离体 IL-13）引起的过度收缩，或 Sundaram 和 Jo 博士在体内过敏性气道疾病模型中证明了气道高反应性。这些保护作用的发生与细胞内肌动蛋白-肌球蛋白交叉桥的变化无关直接调节平滑肌与周围基质的束缚，表明它们可以与目前可用的作用于平滑肌的支气管扩张剂相结合，进一步增强放松效果。在这项提案中，Sundaram 博士和 Jo 提供了初步数据，强调了这一点的重要性。平滑肌束缚蛋白，整合素 α2β1，该整合素的连接可产生针对 IL-13 的保护；他们进一步证明了离体收缩增强和体内气道高反应性。与母体化合物 c15 的原理相同，并与 A2-85 一起显着提高了效力，并且进一步优化本提案中确定的化合物的口服给药。该提案旨在合成和筛选有效且特异性的整合素α2β1小分子抑制剂基于结构的药物设计方法（目标 1）将通过体外优化进一步缩小范围。最后，将根据以下条件选择命中化合物。药代动力学/药效学研究，以优化相关疾病的口服给药和体内测试模型（目标 3）。该提案的 R33 阶段将进一步关注先导系列优化。结合了两位在平滑肌生物学和从头药物设计方面具有专业知识的科学家的努力已经成功地合作设计和开发新型整合素抑制剂，以及一支经验丰富的合作者和顾问团队，他们在临床前药物开发方面拥有丰富的经验。因此，该提案的 R61 阶段旨在提供领先系列，随后的 R33 阶段将进一步关注选择用于治疗控制不佳的哮喘的开发候选药物。