Mitigation of Exaggerated Smooth Muscle Force with Inhibitors of Integrin Alpha2Beta1

项目总结/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）在 加州大学弗朗西斯科分校（UCSF）。这项建议的长期目标是发展 整合素α2β1的新型小分子抑制剂，以破坏气道平滑肌中的力传递， 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，靶向参与平滑蛋白的蛋白质， 在哮喘模型中，肌肉束缚可损害力传递。这些蛋白质的抑制导致 - 防止由致喘细胞因子如IL-13离体诱导的过度收缩，或 过敏性气道疾病模型中的气道高反应性。孙达拉姆博士和乔博士 这些保护作用的发生与细胞内肌动蛋白-肌球蛋白交联的变化无关， 直接调节平滑肌对周围基质的束缚，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组合以进一步增强松弛。 Sundaram博士和Jo博士提出了初步数据，强调了 平滑肌栓系蛋白，整合素α2β1;该整合素的连接导致针对IL-13的保护 增强的离体收缩和体内气道高反应性。他们进一步证明了 原理与母体化合物c15，并与A2-85在效力上有显著改善，和 甚至进一步优化了本建议中鉴定的化合物的口服递送。R61阶段 一项提案旨在合成和筛选整合素α2β1的有效和特异性小分子抑制剂， 基于结构的药物设计方法（Aim 1）。化合物将通过体外优化进一步缩小 和离体验证（目标2）。最后，将根据以下因素选择命中化合物： 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试验 模型（目标3）。本提案的R33阶段将进一步关注电极导线系列优化。这项建议 结合了两位在平滑肌生物学和从头药物设计方面具有专长的科学家的努力， 已经成功地合作设计和开发新型整合素抑制剂， 沿着有经验丰富的合作者和顾问团队，具有临床前药物开发经验。 因此，本提案的R61阶段旨在提供领先系列，随后的R33阶段将 进一步集中于选择用于控制不良的哮喘的治疗用途的开发候选物。

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.