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

恢复 IGF-1 反应的 OA 新型治疗靶点

• 批准号: 7825117
• 负责人: Emma E. Moore
• 金额: $ 33.46万
• 依托单位: OMEROS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825117
• 关键词: Adherent Culture; Affect; Age-Years; Aging; Alginates; Area; Budgets; Cartilage; Cattle; Chemicals; Chemistry; Chondrocytes; Clinical; Collaborations; Degenerative polyarthritis; Development; Disease; Elderly; Employee; Evaluation; Funding; Generations; Goals; Government; Grant; Growth Factor; Growth Factor Inhibition; Homeostasis; Human; Institution; Insulin-Like Growth Factor I; Interleukin-1; Interleukin-4; Joints; Knee joint; Laboratories; Lead; Measures; Mediating; Mediator of activation protein; Modeling; Monitor; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Population; Production; Rattus; Recovery; Regulation; Replacement Arthroplasty; Research; Resistance; Rodent Model; Role; Series; Signal Transduction Inhibitor; Signal Transduction Pathway; Small Interfering RNA; Specificity; Structure-Activity Relationship; Synthesis Chemistry; System; TNF gene; Testing; Therapeutic; Time; Tissue Donors; United States National Institutes of Health; Universities; Wages; Work; aged; aggrecan; analog; clinically relevant; cytokine; design; drug development; effective therapy; forest; in vivo; inhibitor/antagonist; kinase inhibitor; lead series; medical schools; new therapeutic target; normal aging; novel; novel therapeutics; parent grant; programs; public health relevance; repaired; response; small molecule

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.

描述（由申请人提供）：这是一份根据 NOT-OD-09-058 提交的修订申请，题为“NIH 宣布恢复法案基金可用于竞争性修订申请”。在本申请中，我们建议扩大我们的研究计划，以加速开发一种治疗骨关节炎 (OA) 的新型临床候选药物，骨关节炎目前影响 22% 的美国人口，但尚无有效的治疗方法。拟议的扩张包括另外两名合作者，维克森林大学医学院的 Richard Loeser 博士和 SCYNEXIS, Inc. 的 Michael Peel 博士。拟议的预算包括雇用或留住所有三个机构员工的工资支持。母基金 R43AR056911 的目标是开发一种小分子疗法，恢复 OA 和老化软骨细胞对生长因子的反应能力。这种生长因子抵抗已得到充分证明，并被认为会导致基质稳态失衡，而基质稳态失衡是 OA 的标志。用 IL-1 或 TNF 处理原代牛软骨细胞会导致生长因子抵抗，这与衰老和 OA 软骨细胞中描述的情况类似。 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，具有相同特异性的其他抑制剂无法恢复 IGF-1 反应的事实表明必须涉及第二个激酶靶标。母基金的具体目标是：a) 利用 siRNA 敲低来识别抑制 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局调节剂，以及 c) 通过在体内 OA 模型中证明活性抑制剂的功效来建立激酶靶标的临床相关性。在此修订申请中，我们提出了两个额外目标，这将显着推进该项目。首先是通过证明相同的抑制剂可以增强人类 OA 或正常年龄软骨细胞对 IGF-1 和/或 TGF 的反应来确认新激酶靶标的临床相关性，这项工作将在 Loeser 博士的实验室中进行。第二个目标是启动合成化学工作，定义围绕三个先导化学系列的结构活性关系（SAR），以确定最有希望用于先导优化的化学系列并促进目标识别。化合物设计和合成将由 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 a) 鉴定出负责牛软骨细胞合成代谢反应的细胞因子抑制的激酶，b) 验证该激酶在人类 OA 和正常年龄软骨细胞和/或体内啮齿动物模型中的临床相关性 OA，以及 c) 确定了最有前途的化学系列，用于产生具有高效力和选择性的专有临床候选药物。 公众健康相关性：目前，骨关节炎 (OA) 尚无有效治疗方法，骨关节炎是一种严重使人衰弱的疾病，约 50% 的 65 岁以上老年人受到影响。我们的目标是开发一种新型治疗药物，可以刺激骨关节炎关节受损软骨的修复。