Novel compounds for the treatment of systemic sclerosis-associated interstitial lung disease

PROJECT SUMMARY / ABSTRACT Systemic sclerosis interstitial lung disease (SSc-ILD) is a progressive orphan disease highlighted by pulmonary fibrosis leading to a high mortality rate. Currently, there are only two FDA approved SSc-ILD therapies (OFEV and ACTEMRA), both of which have limited efficacy and are mired with safety issues, warranting the development of novel therapeutic targets to treat SSc-ILD. Our preclinical work has identified TGFβ-activated kinase 1 (TAK1) as a key signaling element in fibroinflammatory signaling observed in pulmonary fibrosis. TAK1 plays a critical role in facilitating activation of protein kinase-mediated signaling pathways implicated in the pathogenesis of SSc-ILD, and as a result has emerged as a novel target for regulating SSc-ILD mediated inflammation and fibrotic signaling. Our recent discovery of the takinib scaffold has identified a highly selective (selectivity score = 0.037), potent (IC50 = 2.5nM), and orally bioavailable (%F = 98%) small molecule inhibitor of TAK1 (HS-276). Preclinical studies have demonstrated that TAK1 inhibition attenuates critical TGFβ fibrotic signaling in human-derived fibroblasts, as well as limits pro-inflammatory cytokine signaling in activated human macrophages. Furthermore, HS-276 significantly reduced bleomycin-induced pulmonary fibrosis, in vivo. Here, we will build upon these foundational proof of concept studies and further develop HS-276 for the treatment of SSc-ILD. In order to successfully further develop our program, this project includes the following Specific Aims: Aim 1: In vivo pharmacodynamic studies with HS-276 in two distinct murine lung fibrosis models: (Bleomycin and Tsk1/+). Aim 2: HS-276 safety in bacterial and fungal opportunistic disease models. Aim 3: Completion of key GLP safety and toxicology studies required for submission of an IND. Following successful completion of these aims we will be poised to advance HS-276 towards Phase I clinical trials for the treatment of SSc-ILD.