Sphingosine Kinase as a Target for Cancer Therapy
鞘氨醇激酶作为癌症治疗的靶点
基本信息
- 批准号:7758834
- 负责人:
- 金额:$ 27.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-04-01 至 2012-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAntineoplastic AgentsApoptosisBioavailableBiological ProcessCell LineCell ProliferationCell modelCellsCeramidesDrug KineticsEndothelial CellsGoalsHumanIn VitroLeadMalignant NeoplasmsMediatingMetabolismMethodsModelingMolecular TargetMulti-Drug ResistanceMusOncogenesPhenotypePropertyResistanceRoleSeriesSphingolipidsStructure-Activity RelationshipTherapeutic AgentsToxic effectVascular Endothelial Growth Factorsanalogangiogenesisanti-cancer therapeuticanticancer activitycancer cellcancer therapycomputational chemistrycytotoxicdrug sensitivityin vivoinhibitor/antagonistinnovationkinase inhibitorneoplastic cellnoveloverexpressionresponsesphingosine 1-phosphatesphingosine kinasetumortumor growth
项目摘要
DESCRIPTION (provided by applicant): The goal of this project is to develop inhibitors of human sphingosine kinase (SK) that are effective as anticancer therapeutic agents. We have focused on SK as an innovative molecular target for cancer therapy because of its critical role in sphingolipid metabolism, which is known to regulate tumor cell proliferation and apoptosis, as well as angiogenesis. SK produces sphingosine-1-phosphate, which promotes proliferation, and concurrently depletes ceramide, thereby inhibiting apoptosis. Importantly, studies have demonstrated that SK can act as an oncogene, and that SK activity is crucial for Ras-mediated cell proliferation. Additionally, sphingolipid metabolism has been shown to be involved in resistance to many anticancer drugs. Furthermore, we have recently demonstrated that SK is frequently overexpressed in a variety of human tumors, and that SK inhibitors have antitumor activity in vivo. Because of the pivotal role of SK in regulating tumor growth and drug-sensitivity, we propose to optimize SK inhibitors to be used as anticancer drugs. In Preliminary Studies, we have identified novel compounds with SK inhibitory activity, both in vitro and in intact cells, and have developed efficient methods for the synthesis of analogs of these agents. These compounds are more potent than any other known SK inhibitor, and are cytotoxic toward tumor cells, including cell lines with the multidrug resistance phenotype. Furthermore, examples of these compounds have been shown to be orally bioavailable, and to have in vivo antitumor activity in the absence of toxicity to mice. In this project, we will conduct studies that address the following Specific Aims: 1. To optimize the SK inhibitory activity of these compounds. 2. To evaluate the effects of the SK inhibitors on endothelial and cancer cells. 3. To evaluate the anticancer efficacy of the SK inhibitors in vivo. The compounds synthesized and characterized in this project will provide important new pharmacological probes to determine the roles of SK in biological processes, as well as provide lead compounds that can be developed into new anticancer drugs.
描述(由申请人提供):该项目的目标是开发可有效作为抗癌治疗剂的人鞘氨醇激酶(SK)抑制剂。我们将 SK 视为癌症治疗的创新分子靶点,因为它在鞘脂代谢中发挥着关键作用,众所周知,鞘脂代谢可调节肿瘤细胞增殖和凋亡以及血管生成。 SK 产生 1-磷酸鞘氨醇,促进增殖,同时消耗神经酰胺,从而抑制细胞凋亡。重要的是,研究表明 SK 可以作为癌基因,并且 SK 活性对于 Ras 介导的细胞增殖至关重要。此外,鞘脂代谢已被证明与许多抗癌药物的耐药性有关。此外,我们最近证明SK在多种人类肿瘤中频繁过度表达,并且SK抑制剂具有体内抗肿瘤活性。由于SK在调节肿瘤生长和药物敏感性中的关键作用,我们建议优化SK抑制剂作为抗癌药物。在初步研究中,我们在体外和完整细胞中鉴定出了具有 SK 抑制活性的新型化合物,并开发了合成这些药物类似物的有效方法。这些化合物比任何其他已知的 SK 抑制剂更有效,并且对肿瘤细胞(包括具有多药耐药表型的细胞系)具有细胞毒性。此外,这些化合物的实例已被证明是口服生物可利用的,并且具有体内抗肿瘤活性而不对小鼠产生毒性。在该项目中,我们将开展针对以下具体目标的研究: 1. 优化这些化合物的 SK 抑制活性。 2.评价SK抑制剂对内皮细胞和癌细胞的作用。 3.评价SK抑制剂的体内抗癌功效。该项目合成和表征的化合物将为确定 SK 在生物过程中的作用提供重要的新药理学探针,并提供可开发成新抗癌药物的先导化合物。
项目成果
期刊论文数量(0)
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CHARLES D. SMITH其他文献
CHARLES D. SMITH的其他文献
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{{ truncateString('CHARLES D. SMITH', 18)}}的其他基金
Sphingosine Kinase as a Target for Cancer Therapy
鞘氨醇激酶作为癌症治疗的靶点
- 批准号:
7390630 - 财政年份:2007
- 资助金额:
$ 27.74万 - 项目类别:
Sphingosine Kinase as a Target for Cancer Therapy
鞘氨醇激酶作为癌症治疗的靶点
- 批准号:
7563952 - 财政年份:2007
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$ 27.74万 - 项目类别:
Sphingosine Kinase as a Target for Cancer Therapy
鞘氨醇激酶作为癌症治疗的靶点
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8019619 - 财政年份:2007
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$ 27.74万 - 项目类别:
Sphingosine Kinase as a Target for Cancer Therapy
鞘氨醇激酶作为癌症治疗的靶点
- 批准号:
7263242 - 财政年份:2007
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$ 27.74万 - 项目类别:
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