Pre-clinical development of a small molecule therapeutic for the systemic treatment of idiopathic pulmonary fibrosis - ABSTRACT/PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is the most common type of pulmonary fibrosis. The disease causes scarring and stiffness in the lungs resulting in breathing difficulties and eventual death. IPF affects ~3 million people worldwide, with incidence increasing dramatically with age. Two therapies (pirfenidone and nintedanib) have been shown to slow IPF progression, however, neither therapy stops or reverses the disease, and both have significant side effects that limit tolerability in patients. As such, there is a significant unmet clinical need for the treatment of IPF. In this proposal, we are pharmacologically targeting well-known factors that have been shown to be essential players in IPF development and progression: 1) gp130 signaling and 2) SRC kinases. De novo therapeutic 1. Our first therapeutic candidate is a gp130 small molecule modulator, CX-1015. In vitro and in vivo studies have shown that this molecule targets chronic inflammation and inhibits fibrosis development after injury through a novel mechanism, which is modulation, not complete inhibition, of gp130 signaling. De novo therapeutic 2. Furthermore, we have developed a novel class of SRC kinase recruitment inhibitors (SRis) that prevent cytokine receptor recruitment and subsequent activation of SRC kinases. This technology, termed SRi- 15932, represents a first-in-class approach. The uniqueness of our technology is that unlike other commercially available SRC kinase inhibitors that bind to the catalytic ATP-binding site within the SRC molecule, SRi-15932, in contrast, does not inhibit the catalytic activity of SRC as it binds to the molecule’s allosteric site, which mitigates potential side effects. Just like with CX1015, preliminary studies in vitro and in vivo have demonstrated that inhibition of SRC by SRi-15932 prevents chronic systemic inflammation and fibrosis in various cell types and animal models. Importantly, SRi-15932 has shown to inhibit disease progression in a mouse model of IPF. Our proposed drugs would provide a novel therapeutic advantage over available therapies for IPF. Hypothesis. We propose that our small molecule compounds will not only inhibit the progression of IPF, but can potentially decrease mortality rates by reversing, at least in part, fibrotic lung damage. In the UG3 Phase I, we will explore dose-dependent disease modifying activity and tolerability of both drugs in an aged mouse model of established IPF and chose the most efficacious candidate. The lead candidate will then be evaluated for its anti-fibrotic properties in human lung fibroblasts in vitro. In the UH3 Phase II, the lead candidate will be evaluated for its anti-fibrotic properties in a human ex vivo model of lung slices obtained from late-stage IPF patients. This will be followed by toxicology studies and optimization of formulation of the compound for oral administration. Expected Outcomes. Upon successful completion of the study, we expect our technology to not only inhibit IPF progression, but also reverse the disease, at least in part, which would demonstrate high probability of success in clinical trials and commercialization.
