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

描述(由申请人提供)：这是根据NOT-OD-09-058的修订申请，标题为“NIH宣布恢复法案资金可用于竞争性修订申请。”在这项申请中，我们建议扩大我们的研究计划，以加速开发一种新的临床候选治疗骨性关节炎(OA)，这种疾病目前影响着美国22%的人口，但没有有效的治疗方法。拟议的扩大包括另外两名合作者，维克森林大学医学院的理查德·洛泽博士和Scynexis，Inc.的迈克尔·皮尔博士。拟议的预算包括招聘或留住这三家机构员工的工资支持。父母资助R43AR056911的目标是开发一种小分子疗法，恢复OA和老化的软骨细胞对生长因子的反应能力。这种生长因子抵抗是有充分证据的，并被认为是导致基质稳态失衡的原因，而基质稳态是骨性关节炎的标志。用IL-1或肿瘤坏死因子处理原代牛软骨细胞可导致与衰老和骨关节炎软骨细胞相似的生长因子抵抗。Omeros已经使用牛系统从筛选出的100多种已知抑制剂中鉴定出两种信号转导抑制剂，它们可以完全恢复对IL-1处理的牛软骨细胞的IGF-1反应。这两种抑制剂的主要靶点是相同的；然而，其他具有相同特异性的抑制剂不能恢复IGF-1反应的事实表明，必须涉及第二个激酶靶点。父母资助的具体目标是a)利用siRNA敲除来识别抑制IGF-1反应的激酶靶标，b)确定该激酶是否代表合成代谢功能的全球介体，以及c)通过在活体OA模型中证明活性抑制物的有效性来建立该激酶靶标的临床相关性。在这个修订申请中，我们提出了两个额外的目标，这将显著推进该项目。首先，通过证明相同的抑制剂可以增强人骨关节炎或正常年龄的软骨细胞对IGF-1和/或转化生长因子的反应，以确认新的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努力，以确定三个先导化学系列的结构活性关系(SAR)，以确定最有希望的先导化合物优化和促进目标识别。化合物的设计和合成将由Peel博士和他在Scynexis，Inc.的化学团队完成。完成这项工作后，我们应该已经a)确定了负责细胞因子抑制牛软骨细胞合成反应的激酶(S)，b)验证了该激酶在人类骨关节炎和正常衰老软骨细胞和/或体内啮齿动物模型中的临床相关性，以及c)确定了最有希望产生高效和选择性专有临床候选药物(S)的化学系列。 与公共卫生相关：目前，骨关节炎(OA)还没有有效的治疗方法，这是一种严重衰弱的疾病，在65岁以上的人中约有50%受到影响。我们的目标是开发一种新型的治疗药物，能够促进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.