Preclinical Development of the TAK1 Inhibitor HS-276 for the Treatment of Rheumatoid Arthritis

TAK1 抑制剂 HS-276 用于治疗类风湿关节炎的临床前开发

• 批准号: 10259629
• 负责人: TIMOTHY A HAYSTEAD
• 金额: $ 79.68万
• 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: 2021-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259629
• 关键词: Acute; Affect; Ankylosing spondylitis; Anti-Tumor Necrosis Factor Therapy; Antibodies; Autoimmune; Back; Bioavailable; Biological; Biological Availability; Biological Markers; Biological Response Modifier Therapy; Blocking Antibodies; Bone remodeling; Cells; Chemicals; Chloroquine; Chronic; Collagen Arthritis; Data; Development; Disease; Dose; Drug Kinetics; Elements; Etanercept; Event; Exhibits; Failure; Folic Acid Antagonists; Funding; Goals; Healthcare Systems; Hospitals; Hour; Immune; Immune response; Immunization; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response Pathway; Injections; Injury; Joints; Lead; Life Style; Link; Maximum Tolerated Dose; Mediating; Metabolism; Methotrexate; Mitogen-Activated Protein Kinases; Nuclear; Oncogenic; Oral; Pain; Pathogenesis; Pathway interactions; Patients; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Play; Population; Process; Production; Protein Kinase; Psoriasis; Quality of Care; Quality of life; Readiness; Regulation; Rheumatoid Arthritis; Role; Route; Safety; Series; Signal Pathway; Signal Transduction; Small Business Technology Transfer Research; Steroid therapy; Subcutaneous Injections; Symptoms; Synovitis; TNF gene; Therapeutic; Tissues; Toxic effect; Toxicology; Transforming Growth Factor beta; Treatment Factor; analog; antiarthritic agent; base; chronic inflammatory disease; commercialization; comparative efficacy; cost; cytokine; efficacy study; falls; human model; improved; in vivo; infliximab; inhibitor/antagonist; innovation; intravenous injection; lead candidate; molecular targeted therapies; mouse model; non-compliance; novel; pathogen exposure; preclinical development; preclinical study; programs; protein activation; protein kinase inhibitor; response; safety study; scaffold; side effect; small molecule; societal costs; therapeutic target; tissue repair; treatment strategy; tumorigenesis

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 modulate 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 TGFβ-activated protein kinase 1 (TAK1). 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 and subsequent medicinal chemistry efforts have led to the development of an orally bioavailable, highly selective and potent (IC50 ~2.5nM) inhibitor of TAK1, HS-276. This lead candidate has demonstrated promising results from preliminary efficacy and pharmacokinetic studies which support targeted inhibitor 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 should potentially have limited side effects, in contrast to current targeted RA therapeutics. In order to progress HS-276 towards IND-enabling safety studies, this project involves the following Specific Aims: Aim 1: Establish safety and chemical toxicology of HS-276 in pre-IND-enabling studies. Milestone: Establish route of metabolism, maximum tolerated doses, and define unexpected toxicity issues. Aim 2: Define the therapeutic window for HS- 276 in the CIA mouse model of human RA. Determination of therapeutic window, demonstration of in vivo target engagement and characterization of biomarkers of efficacy. Milestone: Therapeutic window fully defined. Aim 3: Develop a backup series of analogs showing oral bioavailability and increased potency. Milestone: Identify backup analogs in the event of a late stage failure or lack of sufficient efficacy in vivo. Achieving the Specific Aims above will provide a more broadly characterized lead compound, a series of additional analogs, and the necessary data for us to pursue the Commercialization Readiness Pilot Program to fund IND-enabling studies.

项目摘要/摘要 类风湿关节炎(RA)是一种慢性炎症性疾病，在这种疾病中，高度激活的免疫细胞会导致 关节不适应的持续性炎症，导致滑膜炎症和骨重塑。在 在美国，类风湿性关节炎目前影响大约1%的人口，每年的社会总成本负担为 大约392亿美元。在类风湿关节炎中，促炎细胞因子的持续升高会引发慢性组织 损伤和疼痛，最终导致失去行动能力和严重损害患者的生活方式。 肿瘤坏死因子已被证明在类风湿关节炎的发病和促炎中发挥重要作用 信号转导和各种肿瘤坏死因子隔离抗体(如Remicade®和Enbrel®)是这种疾病的适应症。 然而，高达40%的患者对这些疗法没有反应，治疗负担很高 管理成本和不合规率，而且几乎所有这些都存在严重的安全问题，导致大量需求 对于一种具有新型MOA的口服生物利用型替代品，该MOA可以调节肿瘤坏死因子和 减轻类风湿关节炎症状和损害。介导肿瘤坏死因子促生存/炎症反应的关键信号元件 反应途径是蛋白激酶转化生长因子β激活的蛋白激酶1。TAK1在人类免疫系统中起着关键作用 促进蛋白激酶介导的信号转导通路的激活在糖尿病发病机制中的作用 炎症和致癌过程。由于它在这些途径中的关键作用，TAK1已经成为一种 潜在的治疗靶点，用于治疗各种炎症性疾病，包括类风湿性关节炎。我们的 最近发现的Takinib支架和随后的药物化学努力导致了这一发展 口服生物利用度高、选择性强(IC50~2.5 nm)的TAK1抑制剂HS-276。这位领先的候选人 从初步疗效和药代动力学研究中证明了有希望的结果，这支持 靶向TAK1抑制剂是调节肿瘤坏死因子产生和信号转导的有效途径。此外，由于 TAK1的作用似乎主要局限于介导肿瘤坏死因子信号，这样的口服生物利用药应该 与目前的靶向类风湿关节炎疗法相比，其副作用可能是有限的。为了推进HS-276 在促进工业安全研究方面，该项目涉及以下具体目标：目标1：建立安全 和HS-276的化学毒理学在IND启用前的研究中。里程碑：建立代谢途径， 最大耐受量，并定义意外毒性问题。目标2：确定HS的治疗窗口- 276在人RA的CIA小鼠模型中。治疗窗口的确定，体内靶点的展示 功效生物标记物的参与和表征。里程碑：治疗窗口完全确定。目标3： 开发一系列备份类似物，显示口服生物利用度和增强的效力。里程碑：确定 在晚期失败或体内缺乏足够疗效的情况下的后备类似物。实现特定的 上述目标将提供一种更广泛表征的先导化合物，一系列额外的类似物，以及 我们进行商业化准备试验计划以资助支持IND的研究所需的数据。