Targeting Acid Ceramidase for Hepatic Fibrogenesis

ABSTRACT Fibrosis is the common endpoint responsible for liver failure in nearly every form of chronic liver disease, yet there remains no effective treatment for preventing the progression of fibrosis. Our preclinical studies identified a novel antifibrotic target, the enzyme acid ceramidase (aCDase). We demonstrated that depletion or inhibition of aCDase reduces HSC activation, the key step in hepatic fibrogenesis. Moreover, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis in mouse models for liver fibrosis as well as in precision cut liver slices from fibrotic rats and humans. The long-term goal of this project is to develop a potent inhibitor of aCDase for the treatment of hepatic fibrosis. Using structure-based drug design, we have recently discovered a novel series of covalent inhibitors with increased potency and metabolic stability. The objective of this application is to optimize this lead series towards the goal of oral, once-daily dosing for the treatment of hepatic fibrosis. In Aim 1, we will use structure-informed medicinal chemistry approaches to identify a covalent inhibitor based on the lead series with optimal potency, ADME profile, selectivity, and PK properties for oral delivery. In Aim 2, we will use mouse and human models of fibrogenesis to demonstrate the efficacy of the optimized compounds. We have assembled a team with expertise in hepatic fibrosis, medicinal chemistry, and antifibrotic drug development. This work is the first to target the aCDase pathway for the treatment of hepatic fibrogenesis. Our expected outcome is identification of a candidate compound that is ready for nomination for IND-enabling studies. This work is highly significant because it will facilitate a new treatment strategy for patients with hepatic fibrosis, for which no therapies currently exist.