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

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.