Acute Inhibition of TAK1 as a Means to Control COVID-19 Pulmonary Hyperinflammation

项目摘要/摘要 最近流行的新型冠状病毒新冠肺炎对人们的健康和福祉造成了毁灭性的影响 全球范围内的个人，包括到目前为止已确认感染的310万人，以及巨大的影响 对全球医疗体系和整个经济的影响。在美国，已有超过100万例确诊为 目前，包括60,000多人死亡，一些研究估计，新冠肺炎可能会让美国失去医疗保健 在接下来的两年里，系统将耗资5560亿美元。目前还没有批准的治疗新冠肺炎的方法，以及 目前的许多努力意想不到地针对疾病的病毒机制。然而，来自COVID的证据- 19名患者已确认炎症过度是疾病进展和预后的主要因素，以及 降低肿瘤坏死因子、白介素1和白介素6等高炎性介质已成为一种新的治疗手段 新冠肺炎患者的治疗。因此，各种品牌的抗细胞因子免疫调节剂(例如，抗IL-1和 抗IL-6生物制品)目前正在进行临床试验，以治疗新冠肺炎病的并发症，如 急性呼吸窘迫综合征(ARDS)、细胞因子释放综合征和肺炎。然而，所有这些 治疗药物去除了所有靶细胞因子的表达，抑制了导致疾病的免疫病毒检测 进步。因此，存在对口服生物可用小分子疗法的未得到满足的需求，该疗法可以 在活跃的新冠肺炎感染中，将炎性细胞因子减少到正常水平。我们的临床前工作已经确定 转化生长因子β激活的激酶1在肿瘤坏死因子介导的促炎反应中的作用 路径。鉴于最近的临床数据表明肿瘤坏死因子是引发新冠肺炎的主要因素 细胞因子风暴，我们假设TAK1可以靶向预防或大大减轻肺过度炎症 见于新冠肺炎患者。我们最新发现的Takinib支架和随后的药物化学 经过努力，开发出了第一种口服生物利用度、高选择性和强效的药物(IC50~2.5纳米) TAK1抑制剂HS-276。为开发TAK1获得概念验证，作为新冠肺炎诱导的目标 目标1-建立HS-276的治疗效果，以减少 内毒素诱导的肺炎症模型中的炎症反应。里程碑：定义治疗窗口 HS-276在脂多糖诱导的肺炎症模型中的作用。目的2-评价阿司匹林的体内外效应 HS-276对新冠肺炎刺突蛋白(S蛋白)刺激的TAK1的抑制作用里程碑：建立 体外实验表明，HS-276可阻断S蛋白诱导的肿瘤坏死因子的表达，≥的阻断率为赋形剂的50%。目标3- 在SARS-CoV-2模型中确定HS-276减少病毒诱导的ARDS的有效性。里程碑：扩展 HS-276治疗病毒性肺炎的临床前适应证/疗效数据。实现 上面的具体目标将为我们提供必要的数据，以便我们进行NIH SBIR第二阶段申请，以资助 启用IND之前的研究正在向启用IND的研究迈进。

PROJECT SUMMARY/ABSTRACT The recent pandemic of novel coronavirus, COVID-19, has had a devastating effect on the health and well-being of individuals across the globe, including over 3.1 million confirmed infected so far, and a monumental impact on global healthcare systems and economies at large. In the US, over 1,000,000 cases have been confirmed to date, including over 60,000 deaths, and some studies estimate that COVID-19 could cost the US healthcare system $556 billion over the next two years. There are currently no approved treatments for COVID-19, and many current efforts are expectedly targeting the viral mechanisms of disease. However, evidence from COVID- 19 patients has identified hyperinflammation as a major contributor to disease progression and outcomes, and reduction of hyperinflammatory mediators such as TNF, IL-1 and IL-6 has become a novel therapeutic axis for the treatment of COVID-19 patients. Thus, various branded anti-cytokine immunomodulators (e.g., anti-IL-1 and anti-IL-6 biologics) are currently undergoing clinical trials to treat complications of COVID-19 disease such as acute respiratory distress syndrome (ARDS), cytokine release syndrome, and pneumonia. However, all of these therapeutics remove all target cytokine expression, dampening immune-viral detection leading to disease progression. Therefore, there exists an unmet need for an orally bioavailable small molecule therapeutic that can taper inflammatory cytokines to normal levels in an active COVID-19 infection. Our preclinical work has identified TGFβ-activated kinase 1 (TAK1), as a key signaling element within the TNF-mediated proinflammatory response pathway. Given recent clinical data identifying TNF as the primary player in the initiation of the COVID-19 induced cytokine storm, we posit that TAK1 can be targeted to prevent or greatly reduce pulmonary hyperinflammation seen in COVID-19 patients. Our recent discovery of the takinib scaffold and subsequent medicinal chemistry efforts have led to the development of the first orally bioavailable, highly selective and potent (IC50 ~2.5nM) inhibitor of TAK1, HS-276. To obtain proof-of-concept for development of TAK1 as target for COVID-19 induced ARDS, we propose the following Specific Aims: Aim 1 – Establish the therapeutic efficacy of HS-276 to reduce inflammation in the LPS-induced pulmonary inflammatory model. Milestone: Define the therapeutic window of HS-276 in the LPS-induced pulmonary inflammatory model. Aim 2 – Evaluate the in vitro and in vivo effects of TAK1 inhibition with HS-276 in response to COVID-19 spike protein (S-protein) challenge. Milestone: Establish that HS-276 blocks S-protein induced TNF expression by ≥50% compared to vehicle-treated in vitro. Aim 3 – Determine the efficacy of HS-276 to reduce viral-induced ARDS in a SARS-CoV-2 model. Milestone: Expand preclinical indication/efficacy data of HS-276 to treat viral induced pulmonary hyperinflammation. Achieving the Specific Aims above will provide the necessary data for us to pursue a Phase II NIH SBIR application to fund pre-IND-enabling studies en route to IND-enabling studies.