3 DEOXY INOSITOL LIPIDS AND CANCER GROWTH INHIBITION

3 脱氧肌醇脂质与癌症生长抑制

• 批准号: 6497710
• 负责人: GARTH POWIS
• 金额: $ 44.14万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-10 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497710
• 关键词: 3T3 cells; SCID mouse; analog; antineoplastics; biological signal transduction; chemical structure function; chemical substitution; chemical synthesis; cytotoxicity; enzyme activity; enzyme inhibitors; glycerol; immunoprecipitation; lipid metabolism; monosaccharides; oncogenes; pharmacokinetics; phosphatidylinositol 3 kinase; phosphatidylinositols; phosphonate; phosphorylation; protein kinase C; sphingosine; thiophosphate

Phosphatidylinositol-3-kinase (PtdIns-3-kinase) is an important constituent Of growth factor and oncogene signaling pathways and is an attractive target for anticancer drug development. The metabolic products of PtdIns-3-kinase, PtdIns-3-mono and -poly phosphates bind to specific protein domains including the pleckstrin homology (PH) domain, to regulate protein-protein interactions and enzyme activities that are critical to cancer cell growth. We have developed a novel approach to inhibiting PtdIns-3-kinase signaling based on the use of D-3-deoxy-myo- inositol-PtdIns that cannot be metabolized by PtIns-3-kinase and that act as downstream inhibitors of the effects of PtdIns-3- phosphates. We have identified lead D-3-deoxy-PtdIns that inhibit PH domain activation by PtdIns-3-kinase and that have in vivo antitumor activity. We have also synthesized a novel class of 3-deoxy-myo-inositol sphingosine lipids that may act like ceramide, a complex sphingosine lipid that is a key signaling molecule in inducing cancer cell apoptosis. We will develop further both classes of compounds as potential antitumor agents. We will explore modifications of the inositol ring including an examination of carbohydrate surrogates, modification of the glycerol moiety including a study of sphingosine-inositol conjugates, and replacements for the phosphate group. We will use the compounds in mechanistic studies to delineate the role of PtdIns-3-phosphate signaling and inositol-sphingosines in cancer cell growth and death, and we will study the most active compounds as potential antitumor agents.

磷脂酰肌醇-3-激酶(PtdIns-3-Kinase，PtdIns-3-Kinase)是生长因子和癌基因信号通路的重要组成部分，是抗癌药物开发的重要靶点。PtdIns-3-K、PtdIns-3-mono和PtdIns-多聚磷酸盐的代谢产物结合到特定的蛋白质结构域，包括Pleckstrin同源(PH)结构域，以调节对癌细胞生长至关重要的蛋白质-蛋白质相互作用和酶活性。我们开发了一种基于D-3-脱氧-肌醇-PtdIns的抑制PtdIns-3-激酶信号的新方法，D-3-脱氧-肌醇-PtdIns不能被PtIns-3-激酶代谢，并作为PtdIns-3-磷酸作用的下游抑制剂。我们已经鉴定出D-3-脱氧-PtdIns-PtdIns能抑制PtdIns-3-Kinase激活PH域，并具有体内抗肿瘤活性。我们还合成了一类新的3-脱氧-肌醇鞘氨醇磷脂，它可能起神经酰胺的作用，神经酰胺是一种复杂的鞘氨醇脂质，是诱导癌细胞凋亡的关键信号分子。我们将进一步开发这两类化合物作为潜在的抗肿瘤药物。我们将探索肌醇环的修饰，包括碳水化合物替代品的检查，甘油部分的修饰，包括鞘氨醇-肌醇结合物的研究，以及磷酸基团的取代。我们将利用这些化合物在机制研究中阐明PtdIns-3-磷酸信号转导和肌醇-鞘氨醇在癌细胞生长和死亡中的作用，并研究最具活性的化合物作为潜在的抗肿瘤药物。