Development of Neutral Ceramidase Inhibitor Tool Compounds

Colorectal cancer is the third most common cancer in the United States and the second leading cause of all cancer-related deaths. Despite advances in our understanding into the mechanisms that induce colon cancer formation, treatment outcomes are still not very successful. Recently, neutral ceramidases (nCDase) was identified as a therapeutic target for the treatment of colon cancer; with nCDase KO mice displaying marked decreases in adenoma and adenocarcinoma formation in an AOM-induced mouse model of colon cancer. Current substrate mimetics for nCDase exhibit undesirable pharmaceutic properties for systemic delivery; consequently, there is a lack of specific inhibitors with pharmaceutical properties suitable for in vivo studies; impeding their study as a viable cancer target. The specific objective of this proposal is to utilize high- throughput screening (HTS) to identify chemical compounds that modulate nCDase activity and can be used to advance future in vivo studies as a potential therapeutic target.