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

• 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
• 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

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.

项目摘要/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） 加利福尼亚大学旧金山（UCSF）。该提议的长期目标是发展 整合素α2β1的新型小分子抑制剂破坏气道平滑肌的力传播 慢性气道疾病，例如哮喘。 DRS发布的最新数据。 Sundaram和Jo表明，针对光滑的靶向蛋白 肌肉绑扎会损害哮喘模型中的力传播。这些蛋白质的抑制导致 防止哮喘细胞因子（例如IL-13 ex Vivo）或 过敏气道疾病模型的气道高反应性在体内。博士。 Sundaram和Jo已显示 这些受保护的作用是独立于细胞内肌动蛋白肌球蛋白跨桥的变化而发生的 直接调节平滑肌束缚在周围基质上，表明它们可以是 结合当前可用的支气管扩张剂，可在平滑肌上作用，以进一步增强放松。 在此提案中。 Sundaram和Jo提出了初步数据，强调了 平滑肌绑扎蛋白，整联蛋白α2β1；该整合素的连接导致对IL-13的保护 体内收缩后体内和气道高反应性。他们进一步显示了 父母C15的原理，并通过A2-85的效力得到了重大改善，并且 对于本提案中确定的化合物的口服递送的进一步优化。 R61阶段 提案旨在合成和筛选潜在的整合素α2β1的特定小分子抑制剂 基于结构的药水设计方法（AIM 1）。通过体外优化，化合物将进一步缩小 和离体验证（AIM 2）。最后，将根据 药代动力学/药效研究以优化相关疾病中的口服和体内测试 模型（目标3）。该提案的R33阶段将进一步关注潜在客户序列优化。这个建议 结合了两个科学家的努力与平滑肌生物学专业知识和从头毒品设计中的专业知识 已经成功合作在新颖整联蛋白抑制剂的设计和开发方面合作， 以及经验丰富的合作者和顾问团队，具有临床前药物开发方面的经验。 彼此之间，该提案的R61阶段旨在提供铅系列，随后的R33阶段将 进一步专注于选择在控制哮喘不良的治疗用途的发展候选者。