Non-catalytic FAK inhibitors as novel therapeutics for lung fibrosis

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. In Phase I, we developed lead peptide FN-2012 with potent anti-fibrotic effects in IPF cells and lung fibroblasts (IMR90), including reduction in protein levels of collagen, α-SMA, and fibronectin. We also demonstrated significant in vivo efficacy in a mouse model of lung fibrosis. Through this Phase II STTR project, FAKnostics seeks to continue the development of FAK FAT inhibitors as therapy for lung fibrosis. In Aim 1, we will develop chemistry manufacturing & controls for the production of lead peptide FN-2012. In Aim 2, we will perform IND- enabling toxicology studies. In Aim 3, we will comprehensively evaluate the efficacy of FN-2012 in vivo using the aged bleomycin model and human IPF precision cut lung slices. Upon successful completion of these aims, FAKnostics intends to initiate GMP manufacturing and safety pharmacology studies in preparation for an FDA IND application and first-in-human clinical trial.