Development of Novel Inhibitors of Ganglioside Biosynthesis

描述（由申请人提供）：本提案的潜在假设是神经节苷脂生物合成抑制剂将阻止或减缓神经嵴源性肿瘤（神经母细胞瘤、黑色素瘤和星形细胞瘤）的生长。临床研究表明，这些肿瘤类型一致产生一系列改变的神经节苷脂，可以预测其临床进展。遗传和药理学实验表明，神经节苷脂对这些癌症的进展至关重要。总之，这证实了神经节苷脂作为治疗神经母细胞瘤和黑色素瘤的新靶点。在我们的I期项目中，我们不仅开发了我们提出的基于细胞的高通量发现系统，而且我们还完成了74,000种药物样化合物的筛选。在这个II期申请中，我们建议开发我们发现的神经节苷脂生物合成的新型小分子抑制剂。我们将描述hit化合物，测试类似物以确定有希望的hit系列，并在体内测试最有希望的化合物。除了在黑色素瘤模型中的抗癌功效外，体内研究还将表征先导化合物对神经节苷脂生物合成的影响。通过这些研究开发的有效神经节苷脂抑制剂将具有商业潜力，可作为研究工具和新型抗癌疗法的先导化合物。公共卫生相关性：这项拟议研究的目标是开发通过抑制神经节苷脂生物合成起作用的新型抗癌药物。神经节苷是黑色素瘤和神经母细胞瘤快速生长所必需的脂质连接聚糖；然而，目前还没有已知的药物可以特异性地灭活神经节苷脂。这项II期SBIR申请的重点是开发我们在I期SBIR研究中发现的新型神经节苷脂抑制剂。

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. Together 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 inhibitors that we discovered in our Phase I SBIR research.