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Novel AMPK Activators in Breast Cancer Prevention

预防乳腺癌的新型 AMPK 激活剂

基本信息

批准号：
8327114
负责人：
CHING-SHIH CHEN
金额：
$ 19.9万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8327114
关键词：
2,4-thiazolidinedione 70-kDa Ribosomal Protein S6 Kinases Adenosine Monophosphate Adverse effects Agonist Animals Autophagocytosis Biological Markers Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Prevention Cancer Cell Growth Cancer Etiology Cancer Hospital Cancer cell line Carcinogens Cell Survival Cessation of life Chemopreventive Agent Chronic Clinical Management Combinatorial Synthesis Data Defect Development Disease Dose-Limiting Drug Delivery Systems Effectiveness Enzymes Epidemiology Epigenetic Process Epithelial Cells Evaluation Exhibits Family Genetic Goals Growth Factor Heterogeneity Histone Deacetylase Inhibitor Homeostasis Homologous Gene Housing Human Incidence Indole-3-Carbinol Induction of Apoptosis Inflammatory Inhibitory Concentration 50 Interleukin-6 Laboratories Lead Libraries Light Link Longevity Lung MCF7 cell Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Maximum Tolerated Dose Metabolic syndrome Metabolism Metformin Modeling Modification Molecular Molecular Abnormality Molecular Target Oral Other Genetics Parents Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase I Clinical Trials Prevention strategy Production Prostate Protein Dephosphorylation Protein Kinase Protein phosphatase Regulation Research Resources Ribose Safety Screening procedure Second Primary Cancers Signal Pathway Signal Transduction Sirolimus Testing Thiazolidinediones Toxic effect Transgenic Mice Tumor Suppressor Genes Validation Woman analog base cancer cell cancer diagnosis cancer prevention cancer risk cancer therapy carcinogenesis ciglitazone clinically relevant cytokine design diabetic patient drug discovery functional status gastrointestinal in vivo inhibitor/antagonist insulin sensitivity interest macrophage malignant breast neoplasm mouse model novel pre-clinical prevent response small molecule tumor tumor growth tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Accumulating evidence suggests a link between adenosine monophosphate-activated protein kinase (AMPK), a well known regulator of energy homeostasis and insulin sensitivity, and cancer cell growth and survival through the regulation of mTOR signaling pathways, the suppression of inflammatory cytokines, especially interleukin (IL)-6, the stimulation of Akt dephosphorylation through protein phosphatase (PP)2A activation, and modulation of the expression of multiple oncogenes and tumor suppressors. Our screening of an in-house, thiazolidinedione-based focused compound library identified a lead agent, Cpd 53, that despite lacking PPAR agonist activity, activates AMPK and inhibits LPS-induced IL-6 secretion in THP-1 macrophages with low microM potency, and inhibits the proliferation of human breast cancer cells with IC50 of 1 - 2 microM by modulating the functional/expression status of various biomarkers related to AMPK, mTOR-p70S6K signaling, Akt, and IL-6 production. We hypothesize that Cpd 53 can be structurally optimized to generate novel AMPK activators with sub-microM potency that can block mammary tumorigenesis at clinically feasible concentrations and in the absence of dose-limiting toxicities. The following Specific Aims will be carried out to test our hypothesis. Specific Aim 1. To continue the structural modification of Cpd 53 and to conduct mechanistic validation of optimal agents. Cpd 53 will undergo further modifications via combinatorial synthesis with the goal of generating derivatives with sub-5M potency and cancer cell selectivity in different breast cancer cell lines vis-`- vis normal breast epithelial cells. The optimal candidate(s) will be subjected to mechanistic characterizations of signaling targets pertinent to AMPK activation. Specific Aim 2. To assess the in vivo efficacy of two optimized AMPK activators in MCF-7 and MDA-MB-231 xenograft tumor models. We hypothesize that targeting AMPK activation with a small-molecule agent constitutes a potentially successful strategy to suppress breast tumor growth irrespective of the functional status of ER and/or other genetic abnormalities. Two structurally optimized and mechanistically validated derivatives will be tested for in vivo efficacy in comparison to Cpd 53 and metformin. Maximum tolerated doses for each agent will be determined, followed by evaluation of tumor suppressive activity, intratumoral biomarker modulation, and toxicity. Specific Aim 3. To assess the in vivo efficacy of the optimal AMPK activator to block mammary tumorigenesis in a carcinogen-induced mammary tumor model. We hypothesize that the most active AMPK activator identified in Aim 2 will block mammary tumorigenesis in vivo at clinically attainable concentrations and in the absence of limiting toxicity. The safety of chronic oral treatment with this agent will also be examined in carcinogen-untreated animals. As AMPK represents a therapeutically relevant target for the treatment of the metabolic syndrome and cancer, there is a growing interest in the development of novel pharmacological activators for this fuel-sensing enzyme. Cpd 53's ability to target tumor metabolism, and survival signaling via AMPK activation and modulation of mTOR signaling is of high translational value to develop an effective chemopreventive strategy for breast cancer.

描述（申请人提供）：越来越多的证据表明，一磷酸腺苷激活的蛋白激酶（AMPK）（一种众所周知的能量稳态和胰岛素敏感性的调节剂）与癌细胞生长和存活之间的联系是通过调节mTOR信号传导途径，抑制炎性细胞因子，特别是白细胞介素（IL）-6，通过蛋白磷酸酶（PP）2A激活刺激Akt去磷酸化，以及调节多种癌基因和肿瘤抑制因子的表达。我们对内部基于噻唑烷二酮的重点化合物库进行了筛选，发现了一种先导药物Cpd 53，尽管缺乏PPAR激动剂活性，但它仍能激活AMPK并抑制THP-1巨噬细胞中LPS诱导的IL-6分泌，且microM效价较低，并通过调节AMPK相关的各种生物标志物的功能/表达状态抑制人乳腺癌细胞的增殖，IC 50为1 - 2 μ M，mTOR-p70 S6 K信号传导、Akt和IL-6产生。我们假设化合物53可以在结构上优化，以产生具有亚微摩尔效力的新型AMPK激活剂，其可以在临床可行的浓度和不存在剂量限制性毒性的情况下阻断乳腺肿瘤发生。以下具体目标将被执行，以测试我们的假设。具体目标1.继续对化合物53进行结构修饰，并对最佳药物进行机理验证。化合物53将通过组合合成进行进一步修饰，目的是产生在不同乳腺癌细胞系中维斯维斯正常乳腺上皮细胞具有低于5 M效力和癌细胞选择性的衍生物。最佳候选物将经受与AMPK活化相关的信号传导靶标的机制表征。具体目标2。评估两种优化的AMPK激活剂在MCF-7和MDA-MB-231异种移植肿瘤模型中的体内功效。我们假设，靶向AMPK激活与小分子药物构成了一个潜在的成功的策略，以抑制乳腺肿瘤的生长，而不管ER和/或其他遗传异常的功能状态。将测试两种结构优化和机械验证的衍生物与化合物53和二甲双胍相比的体内功效。将确定每种药物的最大耐受剂量，然后评价肿瘤抑制活性、肿瘤内生物标志物调节和毒性。具体目标3。评估最佳AMPK激活剂在致癌物诱导的乳腺肿瘤模型中阻断乳腺肿瘤发生的体内疗效。我们假设，目标2中确定的最活跃的AMPK激活剂将在临床可达到的浓度和没有限制毒性的情况下阻断体内乳腺肿瘤的发生。还将在未接受致癌物治疗的动物中检查该药物长期经口给药的安全性。由于AMPK代表了治疗代谢综合征和癌症的治疗相关靶标，因此对开发这种燃料敏感酶的新型药理学活化剂的兴趣越来越大。化合物53通过AMPK活化和mTOR信号传导的调节靶向肿瘤代谢和存活信号传导的能力对于开发乳腺癌的有效化学预防策略具有高转化价值。