Evaluating the Blood-Brain Barrier Bioavailability and in vivo Efficacy Potential of a Novel TAK1 Inhibitor Targeting Chronic Pain

评估针对慢性疼痛的新型 TAK1 抑制剂的血脑屏障生物利用度和体内疗效潜力

• 批准号: 10151730
• 负责人: TIMOTHY A HAYSTEAD
• 金额: $ 48.1万
• 依托单位: EYDIS BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-08 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10151730
• 关键词: Affect; Analgesics; Anticonvulsants; Antidepressive Agents; Arthritis; Aspirin; Binding; Bioavailable; Biological Availability; Blood - brain barrier anatomy; Central Nervous System Agents; Chronic; Chronic inflammatory pain; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetic Neuropathies; Disease; Distal; Drug Kinetics; Drug user; Economic Burden; Edema; Elements; Event; Exhibits; Female; Freund' s Adjuvant; Funding; Gastrointestinal Hemorrhage; Grant; Health; Healthcare Systems; Hemorrhage; Ibuprofen; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Intestines; Lead; Link; Mechanics; Mediating; Modeling; Myocardial Infarction; Neurons; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Opioid; Oral; PTGS2 gene; Pain; Pain intensity; Parents; Pathogenesis; Patients; Perforation; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphotransferases; Physiological; Play; Process; Production; Protein Kinase; Publishing; Quality of Care; Quality of life; Rattus; Regimen; Risk; Rofecoxib; Role; Route; Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Small Intestines; Streptozocin; Stroke; TNF gene; TNFRSF1A gene; Testing; Therapeutic; Transforming Growth Factor beta; Ulcer; United States National Institutes of Health; Universities; Urate; Ventilatory Depression; Work; addiction; analog; arthritic pain; base; celecoxib; chemokine; chronic pain; chronic pain management; chronic pain patient; comparative efficacy; cost; cytokine; depressive behavior; diabetic; diabetic rat; effective therapy; factor A; gabapentin; gastrointestinal; immune activation; improved; in vivo; inflammatory pain; inhibitor/antagonist; innovation; male; mental state; mouse model; nerve injury; novel; novel therapeutic intervention; opioid epidemic; painful neuropathy; patient population; pre-clinical; preclinical study; prevent; protein activation; protein expression; protein kinase inhibitor; psychological outcomes; receptor; response; safety study; scaffold; side effect; small molecule inhibitor; targeted treatment; tissue injury; treatment strategy

Project Summary / Abstract Chronic pain is a prevalent health concern, affecting up to 100 million people and carrying an economic burden up to $560 billion annually in the US alone, yet treatment options remain limited. Over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) are short-acting and fail to alleviate severe chronic pain, and these conventional drugs carry serious safety concerns regarding gastrointestinal events. In addition, the newer and more selective COX-2 inhibitors such as Celebrex®/celecoxib and Vioxx® carry FDA boxed warnings concerning serious risks of heart attack and stroke. Similarly, longer-acting centrally-targeted therapies such as opioids also have poor efficacy and produce serious side-effects regarding altered mental state, addiction, and respiratory depression. Thus, there is a serious unmet need for alternatives to current treatment options for patients suffering with chronic pain. One of the main drivers of chronic pain is inflammation following tissue injury or nerve injury caused by increased levels of cytokines such as tumor necrosis factor α (TNF), and a positive correlation exists between TNF levels and pain intensity. TNF can bind to its TNFR1 receptor located on the terminals of primary afferent nociceptors to directly increase their activity, and can also stimulate pro-inflammatory cytokine production and immune cell activation. Our preclinical work has identified TGFβ-activated kinase 1 (TAK1), a key signaling element in the mediated TNF pro-survival/inflammatory response pathway. TAK1 plays a crucial role in facilitating activation of protein kinase-mediated signaling pathways implicated in the pathogenesis of chronic pain processes, and as a result has emerged as a novel target for regulating chronic pain and inflammation linked to enhanced TNF signaling. Our recent discovery of the takinib scaffold has identified a highly selective, potent (IC50 ~2.5nM), and orally bioavailable small molecule inhibitor of TAK1 (takinib analog HS-276). Preclinical studies have demonstrated that TAK1 inhibition with parent takinib produces a 9-fold reduction in TNF levels alongside reduced levels of other cytokines and chemokines involved in pro-inflammatory responses. Also, TAK1 inhibition with parent takinib prevented mechanical and thermal heat pain, pain-related depressive behavior, and edema in a model of inflammatory pain. Furthermore, parent takinib treatment in this model reduced pro-inflammatory cytokine and chemokine protein expression. In order to successfully attain proof-of-concept for takinib analog HS-276, this project includes three Specific Aims: Aim 1 – Evaluate the pharmacokinetics of HS-276 regarding blood-brain barrier (BBB) bioavailability. Aim 2 – Determine the established (therapeutic) analgesic potential of HS-276 in a monosodium urate-induced arthritis mouse model of inflammatory pain evidenced by reduction in mechanical and thermal pain, as well as inflammatory cytokines. Aim 3 – Determine the therapeutic analgesic potential of HS-276 in a streptozotocin-induced mouse model of diabetic neuropathy. Achieving the Specific Aims above will provide 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 慢性疼痛是一种普遍存在的健康问题，影响多达 1 亿人并带来经济负担 仅在美国，每年的治疗费用就高达 5600 亿美元，但非处方药的治疗选择仍然有限。 抗炎药 (NSAID) 作用短，无法缓解严重的慢性疼痛，而且这些药物 传统药物在胃肠道事件方面存在严重的安全问题。 更有选择性的 COX-2 抑制剂，例如 Celebrex®/celecoxib 和 Vioxx®，带有 FDA 的黑框警告，涉及以下方面： 同样，阿片类药物等长效中枢靶向治疗也存在心脏病发作和中风的严重风险。 疗效较差，并会产生严重的精神状态、成瘾性和呼吸系统副作用 因此，对于患有抑郁症的患者来说，目前治疗方案的替代方案存在严重未得到满足的需求。 慢性疼痛的主要驱动因素之一是组织损伤或神经损伤后的炎症。 由肿瘤坏死因子α（TNF）等细胞因子水平升高引起，且存在正相关关系 TNF 水平和疼痛强度之间的关系 TNF 可以与其位于初级末端的 TNFR1 受体结合。 传入伤害感受器直接增加其活性，并且还可以刺激促炎细胞因子 我们的临床前工作已鉴定出 TGFβ 激活激酶 1 (TAK1)，一种 TAK1 介导的 TNF 促生存/炎症反应途径中的关键信号传导元件发挥着至关重要的作用。 在促进与发病机制有关的蛋白激酶介导的信号通路的激活中的作用 慢性疼痛过程，因此已成为调节慢性疼痛和 我们最近发现的 takinib 支架发现了与增强的 TNF 信号传导相关的炎症。 高选择性、强效 (IC50 ~2.5nM) 且口服生物可利用的 TAK1 小分子抑制剂（他吉尼类似物） HS-276) 临床前研究表明，母体 takinib 的 TAK1 抑制作用是 9 倍。 TNF 水平降低，同时其他参与促炎的细胞因子和趋化因子水平降低 此外，用母体 takinib 抑制 TAK1 可以预防与疼痛相关的机械性和热热痛。 炎症性疼痛模型中的抑郁行为和水肿此外，母体他克尼治疗。 模型减少了促炎细胞因子和趋化因子蛋白的表达，以成功实现。 takinib 模拟 HS-276 的概念验证，该项目包括三个具体目标： 目标 1 – 评估 HS-276 关于血脑屏障 (BBB) 生物利用度的药代动力学 目标 2 – 确定 在单钠尿酸盐诱导的关节炎小鼠模型中确定了 HS-276 的（治疗）镇痛潜力 机械性疼痛和热痛以及炎症细胞因子的减少证明了炎症性疼痛的减轻。 目标 3 – 确定 HS-276 在链脲佐菌素诱导的小鼠模型中的治疗镇痛潜力 实现上述具体目标将为我们提供必要的数据 寻求 II 期 NIH SBIR 申请，以资助 ​​IND 启用的安全性研究，以进行 I 期临床试验。

项目成果

Transforming Growth Factor-β-Activated Kinase 1 (TAK1) Mediates Chronic Pain and Cytokine Production in Mouse Models of Inflammatory, Neuropathic, and Primary Pain.

转化生长因子-β-激活激酶 1 (TAK1) 介导炎症性、神经性和原发性疼痛小鼠模型中的慢性疼痛和细胞因子的产生。

• 发表时间: 2023-09
• 作者: Scarneo, Scott;Zhang, Xin;Wang, Yaomin;Camacho;Ricano, Jennifer;Hughes, Philip;Haystead, Tim;Nackley, Andrea G
• 通讯作者: Nackley, Andrea G