Improving the Oral Bioavailability and In vivo Efficacy of a Novel TAK1 Inhibitor Targeting 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 一种具有新型MOA的口服生物可利用的替代品，它可以减少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 反应途径是蛋白激酶TAK 1（TGFβ活化蛋白激酶）。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 takinib支架的发现已经确定了TAK 1的高度特异性强效抑制剂（IC 50 ~ 9 nM）， 来自初步疗效研究的有希望的结果支持靶向抑制TAK 1作为有效的 调节TNF产生和信号传导的方法。此外，由于TAK 1的作用似乎主要是 由于局限于介导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， 与包括传统DMARD、生物制剂和尖端JAK/STAT在内的替代疗法相比， 抑制剂（例如，托法替尼）。为了成功实现takinib的概念验证，该项目包括两个 具体目标：目标1（实现口服生物利用度）：基于takinib的共晶体结构，开发一种新的 一系列类似物，在体外保持对TAK 1的选择性，并且在正常大鼠中口服生物可利用。里程碑 - 鉴定至少3种在血清中表现出显著口服生物利用度的选择性类似物。目标2（有效性与 Enbrel®）：评估胶原蛋白中优先的铅分子所产生的抗炎反应 诱导性关节炎（CIA）小鼠模型。里程碑-证明先导化合物分子表现出等同或 在CIA小鼠模型中的疗效优于Enbrel®。实现上述具体目标将提供一个口头 生物可利用的，一流的TAK 1抑制剂先导化合物作为TNF靶向生物制剂的替代品， 用于治疗RA的JAK/STAT抑制剂。这些研究完成后，便会提供所需的数据，让我们继续研究 NIH SBIR II期申请，用于资助IND使能安全性研究进入I期临床试验。

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.