Mitigation of Exaggerated Smooth Muscle Force with Inhibitors of Integrin Alpha2Beta1

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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.