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.

项目摘要 /摘要 慢性疼痛是一个普遍的健康问题 仅在美国，每年最高可达5600亿美元，但治疗方案仍然有限。非处方非甾体类 抗炎药（NSAIDS）是短暂的，无法减轻严重的慢性疼痛，这些 传统药物对胃肠道事件产生严重的安全问题。另外，较新的和 更有选择性的COX-2抑制剂，例如Celebrex®/Celecoxib和Vioxx®随身携带FDA盒装警告 心脏病发作和中风的严重风险。同样，较长作用的集中靶向疗法，例如阿片类药物 效率较差，并且在精神状态，成瘾和呼吸道改变方面产生严重的副作用 沮丧。这是对患者的当前治疗选择的替代方案的严重未满足的需求 慢性疼痛。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，存在阳性相关性 在TNF水平和疼痛强度之间。 TNF可以与位于原发性末端的TNFR1受体结合 传入的伤害感受器直接增加其活性，还可以刺激促炎细胞因子 生产和免疫细胞激活。我们的临床前工作已经确定了TGFβ激活的激酶1（TAK1），A 介导的TNF促生存/炎症反应途径中的关键信号元件。 tak1扮演至关重要的 在支持蛋白激酶介导的信号通路的激活中的作用 慢性疼痛过程，结果已成为调节慢性疼痛和 炎症与增强的TNF信号传导有关。我们最近发现的金尼脚手架已经确定了 高度选择性，潜力（IC50〜2.5nm）和口服生物利用的小分子抑制剂（Takinib Analog） HS-276）。临床前研究表明，tak1抑制takinib产生9倍 降低TNF水平以及其他细胞因子和趋化因子的水平降低 回答。同样，用母体塔克尼抑制tak1抑制了机械和热热疼痛，与疼痛有关 抑郁行为和炎症疼痛模型中的水肿。此外，在此中，父母武尼治疗 模型降低了促炎性细胞因子和趋化因子蛋白表达。为了成功达到 Takinib Analog HS-276的概念证明，该项目包括三个具体目标：AIM 1 - 评估 HS-276的药代动力学有关血脑屏障（BBB）生物利用度。目标2 - 确定 HS-276在单钠诱导的关节炎小鼠模型中建立的（治疗性）镇痛电位 机械和热疼痛以及炎症细胞因子的减少证明了炎症性疼痛。 AIM 3 - 确定HS-276在链蛋白酶诱导的小鼠模型中的治疗性镇痛电位 糖尿病神经病。实现上述特定目标将提供的将为我们提供必要的数据 追求II期NIH SBIR申请，以资助进入I期临床试验的途径。