Identification of the anti-neoplastic target of bioactive FTY720 analogs
生物活性 FTY720 类似物抗肿瘤靶点的鉴定
基本信息
- 批准号:8568587
- 负责人:
- 金额:$ 19.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-01 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAffinity LabelsAgonistAlkynesAnimal ModelAntineoplastic AgentsArchitectureAwardAzidesBindingBioavailableBiochemicalBiologicalBiological AssayBiologyBiotinBradycardiaCancer ModelCancer PatientCellsCeramidesCharacteristicsChemicalsChemistryCoat Protein Complex IComplexCopperCoupledDataDevelopmentDiazomethaneDoseDose-LimitingDown-RegulationDrug CombinationsDrug TargetingDrug resistanceEmployee StrikesExhibitsFDA approvedFundingGrowthHumanHydrocarbonsIn VitroLigandsLymphocyteLymphoidMalignant NeoplasmsMass Spectrum AnalysisModelingMolecularMolecular TargetMultiple SclerosisMusNeoplasm MetastasisNutrientOralOrganPatientsPermeabilityPharmaceutical PreparationsPrimary NeoplasmProbabilityProtein Phosphatase 2A Regulatory Subunit PR53ProteinsProtocols documentationPublishingPyrrolidinesRadiolabeledReactionReceptor ActivationSeriesSpecificitySphingolipidsSphingomyelinsSphingosineSphingosine-1-Phosphate ReceptorStagingStreptavidinStructure-Activity RelationshipTechniquesTestingTherapeuticToxic effectTumor Suppressor ProteinsWaterWorkaffinity labelinganalogappendagebasecancer cellcancer initiationcancer therapycancer typecatalystcrosslinkdesigneffective therapyfunctional groupgel electrophoresisin vivoinhibitor/antagonistkillingsleukemianeoplasticnovelnovel strategiespatient populationpreventprotein complexpublic health relevancepyrrolidineradiotracersuccesstherapeutic developmenttumor
项目摘要
DESCRIPTION (provided by applicant): SUMMARY FTY720 is FDA-approved oral treatment for multiple sclerosis (MS). At the dose used to treat MS, FTY720's effects on sphingosine-1-phosphate receptors result in the sequestration of lymphocytes in secondary lymphoid organs. At much higher doses, many groups have demonstrated that FTY720 is a selective and effective anti-neoplastic agent that works against a wide variety of tumor types. In mouse cancer models at 5-10 mg/kg, FTY720 inhibits the growth of both primary tumors and metastases while exhibiting minimal toxicity. Despite this striking success in animal models, FTY720 cannot be tested in human cancer patients because it triggers profound bradycardia by activating S1P receptors 1 and 3 before the anti-neoplastic dose is reached. However, we have recently demonstrated that the anti-neoplastic effect of FTY720 occurs through an S1P receptor-independent mechanism that includes nutrient transporter down-regulation. While FTY720 analogs that fail to activate S1P receptors have promising anti-neoplastic activity and therapeutic potential, the molecular target of FTY720 in cancer models remains unknown. In this proposal, we will use a chemical biology approach to identify the target of FTY720 and its anti-neoplastic analogs in cancer cells. This project has two Specific Aims: 1) Generate photo-affinity labeling probes from FTY720 analogs that are active in intact cells, and 2) Isolate proteins that specifically interact with the probes using a series of negative controls to identify non-specific binding partners. These probes will include a diazirine to allow UV-crosslinking to the target and an alkyne to covalently couple a biotin to the probe-target complex via "click" chemistry. Determining the molecular target for FTY720 and its analogs in cancer models is a critical step in the development of this novel approach to cancer therapy because it will allow us to: 1) define the molecular characteristics of tumors that will be susceptible to this therapeutic approach so that drugs can be tested in the correct patient populations, 2) uncover potential mechanisms of resistance to these drugs, 3) anticipate potential toxicities, 4) make predictions about drug combinations that are likely to be synergistic, and 5) test our model for how these compounds selectively kill cancer cells using standard molecular and biochemical techniques.
描述(由申请人提供): 摘要 FTY720 是 FDA 批准的多发性硬化症 (MS) 口服治疗药物。在用于治疗 MS 的剂量下,FTY720 对 1-磷酸鞘氨醇受体的作用导致二级淋巴器官中淋巴细胞的隔离。许多研究小组已经证明,在更高剂量下,FTY720 是一种选择性且有效的抗肿瘤药物,可对抗多种肿瘤类型。在小鼠癌症模型中,5-10 mg/kg 剂量的 FTY720 可抑制原发肿瘤和转移瘤的生长,同时表现出最小的毒性。尽管在动物模型中取得了惊人的成功,但 FTY720 无法在人类癌症患者中进行测试,因为它在达到抗肿瘤剂量之前会通过激活 S1P 受体 1 和 3 来引发严重的心动过缓。然而,我们最近证明 FTY720 的抗肿瘤作用是通过 S1P 受体独立机制发生的,其中包括营养转运蛋白下调。虽然无法激活 S1P 受体的 FTY720 类似物具有良好的抗肿瘤活性和治疗潜力,但 FTY720 在癌症模型中的分子靶点仍然未知。在该提案中,我们将使用化学生物学方法来识别癌细胞中FTY720及其抗肿瘤类似物的靶点。该项目有两个具体目标:1) 从在完整细胞中具有活性的 FTY720 类似物生成光亲和标记探针,2) 使用一系列阴性对照分离与探针特异性相互作用的蛋白质,以识别非特异性结合伴侣。这些探针将包括二氮丙啶以允许与靶标进行紫外线交联,以及炔烃以通过“点击”化学将生物素共价偶联至探针-靶标复合物。确定癌症模型中 FTY720 及其类似物的分子靶标是开发这种新型癌症治疗方法的关键一步,因为它将使我们能够:1) 定义对该治疗方法敏感的肿瘤的分子特征,以便可以在正确的患者群体中测试药物,2) 揭示这些药物的潜在耐药机制,3) 预测潜在的毒性,4) 预测药物组合 5)测试我们的模型,了解这些化合物如何使用标准分子和生化技术选择性杀死癌细胞。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Aimee L Edinger其他文献
Aimee L Edinger的其他文献
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{{ truncateString('Aimee L Edinger', 18)}}的其他基金
A novel strategy to overcome drug resistance in cancer
克服癌症耐药性的新策略
- 批准号:
10319166 - 财政年份:2021
- 资助金额:
$ 19.45万 - 项目类别:
A novel strategy to overcome drug resistance in cancer
克服癌症耐药性的新策略
- 批准号:
10609389 - 财政年份:2021
- 资助金额:
$ 19.45万 - 项目类别:
Defining the role of macropinocytosis in solid tumor growth and therapeutic resistance
定义巨胞饮作用在实体瘤生长和治疗耐药中的作用
- 批准号:
10368053 - 财政年份:2020
- 资助金额:
$ 19.45万 - 项目类别:
Defining the role of macropinocytosis in solid tumor growth and therapeutic resistance
定义巨胞饮作用在实体瘤生长和治疗耐药中的作用
- 批准号:
10640820 - 财政年份:2020
- 资助金额:
$ 19.45万 - 项目类别:
Identification of the anti-neoplastic target of bioactive FTY720 analogs
生物活性 FTY720 类似物抗肿瘤靶点的鉴定
- 批准号:
8710117 - 财政年份:2013
- 资助金额:
$ 19.45万 - 项目类别:
Effects of sphingolipids on nutrient transporter expression and bioenergetics
鞘脂对营养转运蛋白表达和生物能学的影响
- 批准号:
8541863 - 财政年份:2010
- 资助金额:
$ 19.45万 - 项目类别:
Effects of sphingolipids on nutrient transporter expression and bioenergetics
鞘脂对营养转运蛋白表达和生物能学的影响
- 批准号:
7769039 - 财政年份:2010
- 资助金额:
$ 19.45万 - 项目类别:
Effects of sphingolipids on nutrient transporter expression and bioenergetics
鞘脂对营养转运蛋白表达和生物能学的影响
- 批准号:
8146063 - 财政年份:2010
- 资助金额:
$ 19.45万 - 项目类别:
Effects of sphingolipids on nutrient transporter expression and bioenergetics
鞘脂对营养转运蛋白表达和生物能学的影响
- 批准号:
8317814 - 财政年份:2010
- 资助金额:
$ 19.45万 - 项目类别:
Effects of sphingolipids on nutrient transporter expression and bioenergetics
鞘脂对营养转运蛋白表达和生物能学的影响
- 批准号:
8730169 - 财政年份:2010
- 资助金额:
$ 19.45万 - 项目类别:
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