Inhibiting Glc Cer biosynthesis to fight cancer growth

University Of Wisconsin Madison, Madison WI

Investigators

Abstract

This proposal encompasses the design, synthesis and evaluation of compounds to inhibit a key enzyme in the process by which cancer spreads through the body. Tumor metastasis relies on an increased level of cell surface carbohydrates, especially glycosphingolipids (GSLs). The enzyme ceramide glucosyltransferase (GlcT-1) catalyses the first step in GSL biosynthesis and its inactivation slows the rate of tumor growth and metastasis. Herein, the design of an entirely new inhibitor of this enzyme is described in the context of a combinatorial approach to generate libraries of GlcT-1 inhibitors. To increase the rate at which these compounds can be tested., we propose a new assay that is an in vitro model for metastasis. We will explore the effect of these inhibitors have on the metastatic abilities of several cancer cell lines under conditions that mimic normal blood flow. The ability of highly metastatic tumor cells to bind with E- and P-selectin will be quantified as a function of the type and amount of inhibitor applied to the tumor cells. The proposed synthetic will be quantified as a function of the type and amount of inhibitor applied to the tumor cells. The proposed synthetic route will also provide homogenous samples of metabolically stable GSLs to help identify which GSL is responsible for adhesion under dynamic flow conditions.