Improving the Oral Bioavailability and In vivo Efficacy of a Novel TAK1 Inhibitor Targeting Rheumatoid Arthritis

提高针对类风湿关节炎的新型 TAK1 抑制剂的口服生物利用度和体内疗效

• 批准号: 9904243
• 负责人: TIMOTHY A HAYSTEAD
• 金额: $ 22.39万
• 依托单位: EYDIS BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904243
• 关键词: Acute; Affect; Ankylosing spondylitis; Anti-Tumor Necrosis Factor Therapy; Anti-inflammatory; Antibodies; Back; Bioavailable; Biological; Biological Availability; Biological Response Modifier Therapy; Bone remodeling; Cells; Chloroquine; Chronic; Collagen-Induced Arthritis; Crohn' s disease; Crystallization; Data; Degenerative polyarthritis; Development; Disease; Disease-Modifying Second-Line Drugs; Elements; Etanercept; Exhibits; Failure; Flare; Folic Acid Antagonists; Funding; Goals; Healthcare Systems; Hospitals; Immune; Immune response; Immunization; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory Response Pathway; Injections; Injury; Joints; Lead; Life Style; Link; MAP3K7 gene; Mediating; Methotrexate; Mitogen-Activated Protein Kinases; Modeling; Nuclear; Oncogenic; Oral; Pain; Pathogenesis; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Population; Process; Production; Protein Kinase; Psoriasis; Quality of Care; Quality of life; Rattus; Regulation; Rheumatoid Arthritis; Role; Route; Safety; Series; Serum; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Steroid therapy; Structure; Subcutaneous Injections; Symptoms; Synovitis; TNF gene; Therapeutic; Tissues; Transforming Growth Factor beta; Treatment Factor; United States National Institutes of Health; Universities; analog; antiarthritic agent; base; cost; cytokine; efficacy study; falls; human model; improved; in vivo; infliximab; inhibitor/antagonist; innovation; intravenous injection; medical schools; molecular targeted therapies; mouse model; non-compliance; novel; pathogen exposure; protein activation; protein kinase inhibitor; response; safety study; scaffold; side effect; societal costs; therapeutic target; tissue repair; treatment strategy

Project Summary / Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease in which hyperactivated immune cells induce maladaptive persistent inflammation in the joints, leading to synovial inflammation and bone remodeling. In the US, RA currently affects roughly 1% of the population and carries a total annual societal cost burden of approximately $39.2 billion. In RA, sustained elevations of pro-inflammatory cytokines elicit chronic tissue damage and pain, which ultimately leads to loss of mobility and significant impairment of the patient’s lifestyle. Tumor necrosis factor (TNF) has been shown to play an important role in RA pathogenesis and pro-inflammatory signaling, and various TNF-sequestering antibodies (e.g., Remicade® and Enbrel®) are indicated for this disease. However, up to 40% of patients fail to respond to these therapies, treatments are burdened with high administration costs and noncompliance rates, and almost all carry serious safety issues, leading to a large need for an orally bioavailable alternative with a novel MOA which can reduce the intracellular effects of TNF and mitigate RA symptoms and damage. A key signaling element in the mediated TNF pro-survival/inflammatory response pathway is the protein kinase TAK1 (TGFβ activated protein kinase). TAK1 plays a crucial role in facilitating activation of protein kinase-mediated signaling pathways implicated in the pathogenesis of inflammatory and oncogenic processes. Because of its critical role in these pathways, TAK1 has emerged as a potential therapeutic target for the treatment of various inflammatory-mediated diseases including RA. Our recent discovery of the takinib scaffold has identified a highly specific potent inhibitor of TAK1 (IC50 ~9nM), and promising results from preliminary efficacy studies have supported targeted inhibition of TAK1 as a valid approach to regulating TNF production and signaling. Additionally, since the role of TAK1 appears to be largely confined to mediating TNF signaling, such an orally bioavailable drug would potentially have limited side effects, in contrast to alternative therapeutics including conventional DMARDs, biologics, and the cutting edge JAK/STAT inhibitors (e.g., tofacitinib). In order to successfully attain proof-of-concept for takinib, the project includes two Specific Aims: Aim 1 (Achieve Oral Bioavailability): Based on the co-crystal structure of takinib, develop a new series of analogs that retain selectivity towards TAK1 in vitro, and are orally bioavailable in normal rats. Milestone – Identify at least 3 selective analogs that exhibit significant oral bioavailability in serum. Aim 2 (Efficacy vs Enbrel®): Evaluate the anti-inflammatory response conferred by prioritized lead molecules in the collagen induced arthritis (CIA) mouse model of RA. Milestone – Demonstrate that the lead molecule exhibits equal or better efficacy than Enbrel® in the CIA mouse model. Achieving the Specific Aims above will provide for an orally bioavailable, first-in-class TAK1 inhibitor lead compound as an alternative to TNF-targeting biologics and JAK/STAT inhibitors for treating RA. Completion of these studies will provide the necessary data for us to pursue a Phase II NIH SBIR application to fund IND-enabling safety studies en route to a Phase I clinical trial.

项目概要/摘要 类风湿性关节炎 (RA) 是一种慢性炎症性疾病，免疫细胞过度活跃会诱发 关节中适应不良的持续炎症，导致滑膜炎症和骨重塑。 在美国，RA 目前影响着大约 1% 的人口，每年的社会总成本负担为 在 RA 中，促炎细胞因子的持续升高会引发慢性组织。 损伤和疼痛，最终导致患者行动能力丧失和生活方式的严重损害。 肿瘤坏死因子 (TNF) 已被证明在 RA 发病机制和促炎中发挥重要作用 信号传导和各种 TNF 隔离抗体（例如 Remicade® 和 Enbrel®）适用于这种疾病。 然而，高达 40% 的患者对这些疗法没有反应，治疗负担高昂 管理成本和违规率，而且几乎都存在严重的安全问题，导致大量需求 寻找一种口服生物可利用的替代品，其具有新型 MOA，可以减少 TNF 的细胞内效应， 减轻 RA 症状和损伤，是 TNF 促生存/炎症介导的关键信号传导元件。 反应途径中发挥着至关重要作用的是蛋白激酶TAK1（TGFβ激活蛋白激酶）。 促进与发病机制有关的蛋白激酶介导的信号通路的激活 由于其在这些途径中的关键作用，TAK1 已成为一种重要的信号通路。 治疗包括 RA 在内的各种炎症介导疾病的潜在治疗靶点。 takinib 支架的发现已经确定了一种高度特异性的有效 TAK1 抑制剂 (IC50 ~9nM)，并且 初步疗效研究的结果有希望支持 TAK1 的靶向抑制作为有效的治疗方法 另外，由于 TAK1 的作用似乎在很大程度上是调节 TNF 产生和信号传导的方法。 仅限于介导 TNF 信号传导，这种口服生物可利用的药物可能具有有限的副作用， 与传统 DMARD、生物制剂和尖端 JAK/STAT 等替代疗法相比 为了成功获得 takinib 的概念验证，该项目包括两种抑制剂。 具体目标： 目标1（实现口服生物利用度）：基于takinib的共晶结构，开发一种新的 一系列在体外保留对 TAK1 选择性的类似物，并且在正常大鼠中具有口服生物利用度。 – 确定至少 3 种在血清中表现出显着口服生物利用度的选择性类似物（目标 2）（功效与效果）。 Enbrel®）：评估胶原蛋白中优先先导分子所赋予的抗炎反应 RA 诱导性关节炎 (CIA) 小鼠模型 - 证明先导分子表现出相同或相同的活性。 比 Enbrel® 在 CIA 小鼠模型中具有更好的功效 实现上述特定目标将提供口服治疗。 生物可利用的一流 TAK1 抑制剂先导化合物，作为 TNF 靶向生物制剂的替代品 JAK/STAT抑制剂治疗RA的研究的完成将为我们的研究提供必要的数据。 II 期 NIH SBIR 申请，用于资助 IND 启用的安全性研究，以进行 I 期临床试验。