Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and fatal fibrotic lung disorder whichdisproportionately affects men and the elderly. Although two drugs (pirfenidone and nintedanib) have recentlygained 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 improvequality of life. Unfortunately, several potential therapies in the fibrosis pipeline have failed to meet their endpointsin recent trials. Hence, we are left with suboptimal treatments and lung transplantation as the only currenttreatment for IPF patients. Importantly, no available therapies "reverse' fibrosis. Focal Adhesion Kinase (FAK) isa non-receptor tyrosine kinase and scaffolding protein that regulates the pro-fibrotic phenotype of lungfibroblasts, including secretion of extracellular matrix proteins (fibronectin and collagen), myofibroblastdifferentiation, cell migration, and resistance to apoptosis. In recent analyses of gene expression in lung tissuefrom 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 beendemonstrated to be critical for the development of lung fibrosis in vitro and in vivo. However, the FAKinhibitors 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 showhigh off-target toxicity, the development of novel FAK inhibitors that target the non-catalytic scaffolding functionor FAT domain of FAK remains a significant unmet clinical need. FAKnostics, LLC has identified a first-in-classseries of stapled peptide-based FAK inhibitors that directly target the FAT domain of FAK. We have preliminarydata that lead peptide FN-2023 causes potent anti-fibrotic effects in lung fibroblasts (IMR90), including reductionin 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, wewill optimize lead peptide FN-2023 to improve ADMET properties. In Aim 2, we will characterize optimizedpeptides for anti-fibrotic effects on lung fibroblasts and precision cut lung slices (PCLS). In Aim 3, we willevaluate in vivo pharmacokinetics of top optimized peptides and test using an in vivo efficacy model of lungfibrosis (bleomycin injury model). Ultimately, this project will result in optimized FAK FAT peptides that showimproved ADMET properties and efficacy in a mouse model of lung fibrosis, supporting further preclinicaldevelopment in a future Phase II project.
Public Health Relevance Statement: Project Narrative
Idiopathic pulmonary fibrosis (IPF) is a highly fatal fibrotic lung disorder that has a poor prognosis and limited
current therapeutic options. FAKnostics, LLC is developing a platform of stapled peptide-based inhibitors that
target focal adhesion kinase (FAK), a protein which is responsible for driving the hallmarks of lung fibrosis,
including secretion of collagen and fibronectin. This project will provide proof-of-concept evidence supporting the
use of these FAK peptides for the treatment of IPF.
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