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

项目总结/摘要 最近的新型冠状病毒COVID-19大流行对健康和福祉造成了毁灭性的影响， 地球仪的感染人数，包括迄今为止确诊的310多万人， 对全球医疗系统和经济的影响。在美国，已有超过100万例确诊病例， 截至目前，包括超过60，000人死亡，一些研究估计，COVID-19可能会使美国的医疗保健成本上升。 在未来两年内，该系统将投入5560亿美元。目前没有批准的COVID-19治疗方法， 目前的许多努力都是针对疾病的病毒机制。然而，新冠病毒的证据- 19例患者已确定炎症过度是疾病进展和结局的主要因素， 减少高炎症介质如TNF、IL-1和IL-6已经成为一种新的治疗手段， 治疗COVID-19患者。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生物制剂）目前正在进行临床试验，以治疗COVID-19疾病的并发症， 急性呼吸窘迫综合征（ARDS）、细胞因子释放综合征和肺炎。但这一切 治疗剂去除所有靶细胞因子表达，抑制导致疾病的免疫病毒检测 进展因此，存在对口服生物可利用的小分子治疗剂的未满足的需求，所述小分子治疗剂可以 在活动性COVID-19感染中将炎性细胞因子降至正常水平。我们的临床前工作已经确定 TGFβ激活的激酶1（TAK 1），作为TNF介导的促炎反应中的关键信号元件 通路鉴于最近的临床数据确定TNF是COVID-19诱导的 细胞因子风暴，我们证实TAK 1可以靶向预防或大大减少肺过度炎症 在COVID-19患者中发现。我们最近发现的takinib支架和随后的药物化学 努力导致第一个口服生物利用度，高选择性和有效性（IC 50 ~2.5nM）的发展 TAK 1抑制剂HS-276。为获得开发TAK 1作为COVID-19诱导靶点的概念验证 目的1 -确定HS-276对降低急性呼吸窘迫综合征（ARDS）的治疗效果， LPS诱导的肺部炎症模型中的炎症。里程碑：定义治疗窗口 HS-276在LPS诱导的肺部炎症模型中的作用。目的2 -评价体外和体内效应 HS-276对COVID-19刺突蛋白（S蛋白）激发的TAK 1抑制作用。里程碑：建立 与溶剂处理相比，HS-276在体外阻断S蛋白诱导的TNF表达≥50%。目标3 - 确定HS-276在SARS-CoV-2模型中减少病毒诱导的ARDS的功效。里程碑：扩展 HS-276治疗病毒诱导的肺部炎症过度的临床前适应症/疗效数据。实现 上述具体目标将为我们提供必要的数据，以进行第二阶段NIH SBIR申请， IND启动前研究正在进行IND启动研究。

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.