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

项目总结/摘要 类风湿性关节炎（RA）是一种慢性炎症性疾病， 关节中的适应不良的持续性炎症，导致滑膜炎症和骨重塑。在 在美国，RA目前影响约1%的人口，每年的社会总成本负担为 约392亿美元。在类风湿关节炎中，促炎细胞因子的持续升高引起慢性组织炎性反应， 损伤和疼痛，最终导致丧失活动能力和严重损害患者的生活方式。 肿瘤坏死因子（TNF）在RA发病机制中起重要作用， 信号传导，和各种TNF-螯合抗体（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，治疗负担沉重， 管理成本和违规率，几乎所有都存在严重的安全问题，导致大量的需求 对于具有新型MOA的口服生物可利用的替代物，其可以调节TNF的细胞内效应， 减轻RA症状和损害。在介导的TNF促存活/炎症中的关键信号传导元件 这种反应途径是蛋白激酶TGFβ激活的蛋白激酶1（TAK 1）。TAK 1在以下方面起着至关重要的作用 促进蛋白激酶介导的信号通路的激活， 炎症和致癌过程。由于其在这些途径中的关键作用，TAK 1已成为一种新的途径。 潜在的治疗靶点，用于治疗各种炎症介导的疾病，包括RA。我们 最近发现的takinib支架和随后的药物化学努力导致了 一种口服生物利用度高、选择性强且有效的TAK 1抑制剂HS-276。这位主要候选人 已从初步疗效和药代动力学研究中证明了有希望的结果， TAK 1的靶向抑制剂作为调节TNF产生和信号传导的有效方法。此外，由于 TAK 1的作用似乎主要局限于介导TNF信号传导，这种口服生物可利用的药物应该 潜在地具有有限的副作用。为了进行HS-276 为了使IND能够进行安全性研究，该项目涉及以下具体目标：目标1：建立安全性 和化学毒理学研究中的HS-276。里程碑：建立代谢途径， 最大耐受剂量，并确定意外的毒性问题。目的2：定义HS的治疗窗- 276在人RA的CIA小鼠模型中。治疗窗的确定，体内靶点的证明 有效性生物标志物的参与和表征。里程碑：治疗窗完全定义。目标3： 开发一系列类似物的备份，显示口服生物利用度和增加的效力。里程碑：识别 在后期失效或缺乏足够的体内功效的情况下使用备用类似物。实现具体 以上目的将提供更广泛表征的先导化合物、一系列另外的类似物和其药学上可接受的盐。 必要的数据，以便我们继续开展商业化准备试点计划，为IND支持研究提供资金。

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.