Mitigation of Exaggerated Smooth Muscle Force with Inhibitors of Integrin Alpha2Beta1

项目摘要/摘要 这是为Aparna Sundaram博士(助理教授， 医学系)和Jo博士(药物化学系助理教授)于 加州大学旧金山分校(UCSF)。这项提议的长期目标是发展 新型小分子整合素α-2-β-1拮抗剂阻断大鼠气道平滑肌力传递 慢性呼吸道疾病，如哮喘。 Sundaram博士和Jo博士最近发表的数据表明，靶向蛋白参与平滑 肌肉拴系可损害哮喘模型中的力量传递。抑制这些蛋白质会导致 对哮喘细胞因子如IL-13体外诱导的过度收缩的保护，或 体内过敏性呼吸道疾病模型中的气道高反应性。Sundaram博士和Jo博士已经证明 这些保护作用独立于细胞内肌动蛋白-肌球蛋白交叉桥接的变化而发生 直接调节平滑肌与周围基质的捆绑，这表明它们可以 与目前可用的作用于平滑肌的支气管扩张剂相结合，进一步增强松弛。 在这项提案中，Sundaram博士和Jo博士提供了初步数据，强调了 平滑肌拴系蛋白，整合素α2β1；连接该整合素可产生对IL-13的保护作用 增强体外收缩和体内呼吸道高反应性。他们进一步证明了 与母体化合物C15的原理，并在A2-85的效力方面取得了显著的改进，以及 使用本提案中确定的化合物进一步优化口服给药。这方面的R61阶段 一项旨在合成和筛选整合蛋白α2β1的有效和特异的小分子抑制剂的提案 基于结构的药物设计方法(目标1)。化合物将通过体外优化进一步缩小范围 和体外验证(目标2)。最后，命中化合物将根据以下条件进行选择 优化相关疾病口服给药和体内试验的药代动力学/药效学研究 模型(目标3)。该提案的R33阶段将进一步侧重于铅系列的优化。这项建议 结合了两位在平滑肌生物学和从头开始药物设计方面有专长的科学家的努力 已经在设计和开发新型整合素抑制剂方面成功地合作， 以及一支经验丰富的合作者团队和具有临床前药物开发经验的顾问。 因此，本提案的R61阶段旨在提供领导系列，随后的R33阶段将 进一步侧重于选择一种用于治疗控制不佳的哮喘的发育候选药物。

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.