Non-catalytic FAK inhibitors as novel therapeutics for lung fibrosis

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PROJECT ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and fatal fibrotic lung disorder which disproportionately affects men and the elderly. Although two drugs (pirfenidone and nintedanib) have recently gained FDA-approval for IPF and progressive fibrosing lung disorders related to connective tissue diseases (rheumatoid arthritis and scleroderma, more common in younger women), these drugs are by no means curative. In fact, these therapies show only a modest reduction in the rate of lung function decline and do not improve quality of life. Unfortunately, several potential therapies in the fibrosis pipeline have failed to meet their endpoints in recent trials. Hence, we are left with suboptimal treatments and lung transplantation as the only current treatment for IPF patients. Importantly, no available therapies ‘reverse’ fibrosis. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase and scaffolding protein that regulates the pro-fibrotic phenotype of lung fibroblasts, including secretion of extracellular matrix proteins (fibronectin and collagen), myofibroblast differentiation, cell migration, and resistance to apoptosis. In recent analyses of gene expression in lung tissue from IPF patients, FAK is highly upregulated in both early IPF and advanced IPF compared to health controls. Moreover, the scaffolding function of the Focal Adhesion Targeting (FAT) domain of FAK has been demonstrated to be critical for the development of lung fibrosis in vitro and in vivo. However, the FAK inhibitors developed to date only target its kinase enzyme and ignore FAK’s role as a scaffolding protein. Because current FAK-kinase inhibitors do not inhibit key FAT domain interactions in lung fibroblasts and show high off-target toxicity, the development of novel FAK inhibitors that target the non-catalytic scaffolding function or FAT domain of FAK remains a significant unmet clinical need. FAKnostics, LLC has identified a first-in-class series of stapled peptide-based FAK inhibitors that directly target the FAT domain of FAK. We have preliminary data that lead peptide FN-2023 causes potent anti-fibrotic effects in lung fibroblasts (IMR90), including reduction in protein levels of α-SMA, fibronectin, and collagen. The goal of this Phase I STTR is to demonstrate proof- of-concept for the use of these novel FAK FAT inhibitors as therapeutics of lung fibrosis. In Aim 1, we will optimize lead peptide FN-2023 to improve ADMET properties. In Aim 2, we will characterize optimized peptides for anti-fibrotic effects on lung fibroblasts and precision cut lung slices (PCLS). In Aim 3, we will evaluate in vivo pharmacokinetics of top optimized peptides and test using an in vivo efficacy model of lung fibrosis (bleomycin injury model). Ultimately, this project will result in optimized FAK FAT peptides that show improved ADMET properties and efficacy in a mouse model of lung fibrosis, supporting further preclinical development in a future Phase II project.