A novel therapeutic target for OA that restores IGF-1 responses

描述（由申请人提供）：这是一个修订申请下的NOT-OD-09-058题为“NIH宣布恢复法资金的竞争性修订申请的可用性。“在这项申请中，我们建议扩大我们的研究计划，以加速开发一种用于治疗骨关节炎（OA）的新型临床候选药物，这种疾病目前影响着22%的美国人口，但没有有效的治疗方法。拟议的扩展包括两个额外的合作者，维克森林大学医学院的Richard Loeser博士和SCYNEXIS公司的Michael Peel博士。拟议预算包括在所有三个机构雇用或留住雇员的薪金支助。母基金R43 AR 056911的目标是开发一种小分子治疗剂，恢复OA和老化软骨细胞对生长因子的反应能力。这种生长因子抵抗是有据可查的，并被认为有助于基质稳态的失衡，这是OA的标志。用IL-1或TNF处理原代牛软骨细胞导致生长因子抗性，其与在老化和OA软骨细胞中描述的相似。Omeros使用牛系统从筛选的100多种已知抑制剂中鉴定出两种信号转导抑制剂，它们可以完全恢复IGF-1对IL-1处理的牛软骨细胞的反应。这两种抑制剂的主要靶标是相同的;然而，具有相同特异性的其他抑制剂不能恢复IGF-1应答的事实表明必须涉及第二激酶靶标。母基金的具体目的是a）利用siRNA敲除来鉴定抑制IGF-1反应的激酶靶点，B）确定该激酶是否代表合成代谢功能的全局介体，以及c）通过证明活性抑制剂在体内OA模型中的功效来建立激酶靶点的临床相关性。在本修订申请中，我们提出了两个额外的目标，这将大大推进这个项目。首先是通过证明相同的抑制剂可以增强人OA或正常老化软骨细胞对IGF-1和/或TGF-β的反应来确认新型激酶靶点的临床相关性，这项工作将在Loeser博士的实验室进行。第二个目标是启动合成化学的努力，以确定结构活性关系（SAR）围绕三个铅化学系列，以确定最有前途的一个铅优化，并促进目标识别。化合物设计和合成将由Peel博士及其在SCYNEXIS，Inc.的化学团队完成。在完成这项工作时，我们应该a）鉴定出负责牛软骨细胞中合成代谢反应的细胞因子抑制的激酶，B）验证了该激酶在人OA和正常老化软骨细胞和/或OA的体内啮齿动物模型中的临床相关性，以及c）鉴定出用于产生具有高效力和选择性的专有临床候选物的最有前景的化学系列。 公共卫生相关性：目前，骨关节炎（OA）没有有效的治疗方法，这是一种严重的衰弱性疾病，影响了大约50%的65岁以上的人。我们的目标是开发一种新的治疗药物，可以刺激OA关节受损软骨的修复。

DESCRIPTION (provided by applicant): This is a revision application under NOT-OD-09-058 entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications." In this application we propose to expand our research program in order to accelerate the development of a novel clinical candidate for the treatment of osteoarthritis (OA), a disease that currently affects 22% of the US population but has no effective treatment. The proposed expansion includes two additional collaborators, Dr. Richard Loeser at the Wake Forest University School of Medicine and Dr. Michael Peel at SCYNEXIS, Inc. The proposed budget includes salary support to hire or retain employees at all three institutions. The goal of the parent grant R43AR056911 is to develop a small molecule therapeutic that restores the ability of OA and aged chondrocytes to respond to growth factors. This growth-factor resistance is well-documented and is thought to contribute to the imbalance of matrix homeostasis that is the hallmark of OA. Treatment of primary bovine chondrocytes with IL-1 or TNF leads to a growth factor resistance that is similar to that described in aging and OA chondrocytes. Omeros has used the bovine system to identify two signal transduction inhibitors, from over 100 known inhibitors that were screened, that can completely restore the IGF-1 response to IL-1 treated bovine chondrocytes. The primary target for these two inhibitors is the same; however, the fact that other inhibitors with the same specificity cannot restore the IGF-1 response indicates that a second kinase target must be involved. The specific aims of the parent grant are a) to utilize siRNA knockdowns to identify the kinase target that inhibits the IGF-1 response, b) to determine if this kinase represents a global mediator of anabolic functions, and c) to establish clinical relevance of the kinase target by demonstrating efficacy of an active inhibitor in an in vivo OA model. In this revision application, we propose two additional goals that will significantly advance this project. The first is to confirm the clinical relevance of the novel kinase target by demonstrating that the same inhibitors can enhance the response of human OA or normal-aged chondrocytes to IGF-1 and/or TGF¿, work that will be performed in the laboratory of Dr. Loeser. The second goal is to initiate synthetic chemistry efforts to define the structure activity relationships (SAR) around three lead chemical series in order to identify the most promising one for lead optimization and to facilitate target identification. Compound design and synthesis will be done by Dr. Peel and his chemistry team at SCYNEXIS, Inc. At the completion of this work we should have a) identified the kinase(s) that is responsible for cytokine inhibition of anabolic responses in bovine chondrocytes, b) validated the clinical relevance of this kinase in human OA and normal-aged chondrocytes and/or an in vivo rodent model of OA, and c) identified the most promising chemical series for the generation of a proprietary clinical candidate(s) with high potency and selectivity. PUBLIC HEALTH RELEVANCE: Currently, there is no effective treatment for osteoarthritis (OA), a severely debilitating disease that affects approximately 50% of those over 65 years of age. Our goal is to develop a novel therapeutic drug that can stimulate repair of damaged cartilage in the OA joint.