Mechanism of Chemoprevention Action and SAR of a Tetrahydroisoquinoline Riboside

四氢异喹啉核苷的化学预防作用机制和比吸收率

• 批准号: 7777887
• 负责人: John K Buolamwini
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777887
• 关键词: Accounting; Animal Model; Biochemical; Biological Assay; Cells; Chemoprevention; Chemopreventive Agent; DNA Binding; DNA-Binding Proteins; Development; Funding; Goals; Grant; Human; In Vitro; Inbred SENCAR Mice; Investigation; Laboratories; Lead; MAP Kinase Signaling Pathways; MAPK14 gene; MAPK8 gene; Malignant Neoplasms; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Biology; Molecular Target; Mus; Nucleoside Transporter; Pathway interactions; Play; Process; Protein Kinase C; Relative (related person); Reporter; Research; Role; Seeds; Signal Pathway; Skin; Skin Cancer; Skin Carcinogenesis; Staging; Structure-Activity Relationship; Testing; Tetrahydroisoquinolines; Transcription Factor AP-1; Tumor Promotion; analog; cancer chemoprevention; carcinogenesis; cell growth; chemical synthesis; design; drug development; in vivo; inhibitor/antagonist; novel; pre-clinical; programs; purine riboside; riboside; success; tumorigenic

DESCRIPTION (provided by applicant): Promotion agents with a structure-activity relationship (SAR) that points to some mechanism(s) other than NT inhibition. For example, among novel tetrahydroisoquinoline riboside NT inhibitors tested as anti-tumor promotion agents in the JB6 P+ carcinogenesis model, the relative order of potency with regard to anti-promotion activity was: Compound 23 > Compound 3 > Compound 4, whereas the NT inhibitory potency order was the opposite, with Compound 4 being the most potent (Ki = 0.45 nM) followed by Compound 3 (Ki = 15 nM) and then followed by Compound 23, the least potent (Ki = 300 nM). Upon further investigation with Compound 23, we have shown that in addition to inhibiting TPA-induced tumorigenic transformation, it also inhibits TPA-induced AP-1 transcription factor activation, which has been shown to have a major role in TPA-induced tumor promotion in the JB6 mouse epidermal cell carcinogenesis model, as well as in many other in vitro and in vivo carcinogenesis processes. Thus, in this application, we propose to initiate an investigation of the mechanisms of action of compound 23, as well as conduct antitumor promotion SAR and test the compounds' cancer chemopreventive potential in an in vivo mouse skin carcinogenesis model. The specific aims are: 1) to synthesize and test new aromatic and heterocyclic analogs of Compound 23, 2) to investigate interference with AP-1 DNA binding, and MAP kinase signaling pathways that might account for the possible AP-1-dependent antitumor promotion activity of the compounds, and 3) to evaluate the best compound from Aim 2 in an in vivo mouse skin carcinogenesis model. AP-1-SEAP JB6 reporter cells created by us will be used for the in vitro investigations of SAR and mechanism. We will use the AP-1-SEAP reporter and anchorage independent cell growth clonogenic transformation assays to test the potential chemopreventive activity of new compounds to be synthesized activity. Interference with AP-1 DNA binding, protein kinase C, as well as the role of the mitogen-activated protein kinases (MAPKs) ERK, p38 and JNK, known to be upstream of AP-1, will be analyzed. The SENCAR mouse skin two-stage carcinogenesis model will be used to assess the in vivo anti-tumor promotion activity of this class of compounds in attempts to identify potential lead compounds for preclinical optimization. The success of this research program may lead to the identification of novel promising agents for skin cancer chemoprevention.

描述（由申请人提供）： 具有结构-活性关系 (SAR) 的促进剂表明除 NT 抑制之外的某些机制。例如，在 JB6 P+ 致癌模型中测试作为抗肿瘤促进剂的新型四氢异喹啉核苷 NT 抑制剂中，抗促进活性的相对效力顺序为：化合物 23 > 化合物 3 > 化合物 4，而 NT 抑制效力顺序则相反，化合物 4 的效力最强（Ki = 0.45 nM）。 首先是化合物 3 (Ki = 15 nM)，然后是效力最弱的化合物 23 (Ki = 300 nM)。通过对化合物 23 的进一步研究，我们发现，除了抑制 TPA 诱导的致瘤转化外，它还可以抑制 TPA 诱导的 AP-1 转录因子激活，在 JB6 小鼠表皮细胞癌变模型以及许多其他体外和体内致癌过程中，AP-1 转录因子激活在 TPA 诱导的肿瘤促进中起主要作用。因此，在本申请中，我们建议开始研究化合物23的作用机制，并进行抗肿瘤促进SAR并在体内小鼠皮肤癌模型中测试化合物的癌症化学预防潜力。具体目标是：1) 合成和测试化合物 23 的新芳香族和杂环类似物，2) 研究对 AP-1 DNA 结合和 MAP 激酶信号通路的干扰，这可能解释了化合物可能具有的 AP-1 依赖性抗肿瘤促进活性，以及​​ 3) 在体内小鼠皮肤癌模型中评估来自 Aim 2 的最佳化合物。我们创建的AP-1-SEAP JB6报告细胞将用于SAR及其机制的体外研究。我们将使用 AP-1-SEAP 报告基因和贴壁独立细胞生长克隆转化测定来测试要合成的新化合物的潜在化学预防活性。将分析对 AP-1 DNA 结合、蛋白激酶 C 的干扰，以及已知为 AP-1 上游的丝裂原激活蛋白激酶 (MAPK) ERK、p38 和 JNK 的作用。 SENCAR小鼠皮肤两阶段癌变模型将用于评估此类化合物的体内抗肿瘤促进活性，试图识别潜在的先导化合物以进行临床前优化。该研究计划的成功可能会导致发现新的有前途的皮肤癌化学预防药物。