Development of Novel Inhibitors of Ganglioside Biosynthesis

DESCRIPTION (provided by applicant): The underlying hypothesis of this proposal is that inhibitors of ganglioside biosynthesis will prevent or slow the growth of neural crest-derived tumors (neuroblastoma, melanoma, and astrocytoma). Clinical studies have shown that these tumor types consistently produce an altered array of gangliosides that can predict their clinical progression. Genetic and pharmacological experiments demonstrate that gangliosides are essential for the progression of these cancers. Togeth er this validates gangliosides as a novel target for the treatment of neuroblastoma and melanoma. In our Phase I program, we not only developed the cell based high throughput discovery system that we proposed, but we also completed a screen of 74,000 drug- like compounds. In this Phase II application, we propose to develop the novel small molecule inhibitors of ganglioside biosynthesis that we discovered. We will characterize the hit compounds, test analogs to identify promising hit series, and test the most promising compounds in vivo. The in vivo studies will characterize the effects of the lead compounds on ganglioside biosynthesis in addition to anticancer efficacy in a melanoma model. Effective ganglioside inhibitors developed through these studies will have commercial potential as research tools and as lead compounds for novel anticancer therapies. PUBLIC HEALTH RELEVANCE:The goal of the proposed research is to develop novel anticancer drugs that work by inhibiting ganglioside biosynthesis. Gangliosides are lipid linked glycans that are required by melanoma and neuroblastoma for their rapid growth; however, there are no known agents that can specifically inactivate gangliosides. This Phase II SBIR application focuses on developing novel ganglioside inhibi tors that we discovered in our Phase I SBIR research.