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.