Identifying Small Molecules To Probe the Role of Heat Shock Factor 1 in Cancer

鉴定小分子以探究热休克因子 1 在癌症中的作用

• 批准号: 7694213
• 负责人: LUKE J WHITESELL
• 金额: $ 2.5万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694213
• 关键词: Address; Affinity; Affinity Chromatography; Animals; Biochemical; Biological; Biological Assay; Biological Factors; Biology; Cancer Biology; Cell Line; Cells; Chemicals; Chemoprevention; Collaborations; Collection; Complex; Consensus; DNA; DNA Binding; Dependence; Development; Development Plans; Doxycycline; Embryo; Energy Metabolism; Environment; Eukaryota; Family; Fibroblasts; Fluorescence; Future; Gene Expression; Genetic; Genetic Techniques; Genetic Transcription; Growth; Heat shock proteins; Heat-Shock Proteins 70; Heat-Shock Proteins 90; Heat-Shock Response; Human; Institutes; Lead; Lesion; Light; Luciferases; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammals; Mediating; Metabolism; Methods; Molecular Bank; Molecular Chaperones; Mus; Neurodegenerative Disorders; Normal Cell; Oncogenes; Oncogenic; Organism; Pathway interactions; Pharmaceutical Preparations; Post-Translational Protein Processing; Process; Production; Proteins; Reagent; Regulation; Reporter; Reporting; Response Elements; Role; Screening procedure; Shapes; Signal Transduction; Specificity; Stress; Structure-Activity Relationship; System; Therapeutic; Transactivation; Translations; Tumor Cell Line; United States National Institutes of Health; Work; analog; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; cost; cytotoxicity; design; experience; genome-wide; heat-shock factor 1; high throughput screening; improved; inhibitor/antagonist; innovation; insight; interest; internal control; miniaturize; mouse model; neoplastic cell; novel; novel therapeutics; pre-clinical; preclinical study; programs; promoter; protein expression; protein folding; public health relevance; repository; response; small molecule; thermal stress; tool; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The heat shock response (HSR) is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding environment through the induction of heat shock proteins but as more recent work has shown to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this response is regulated primarily by Heat Shock Factor 1 (HSF1), a transcription factor whose mode of action has been conserved in broad outline across all eukaryotes. Surprisingly, our recent work has shown that the many beneficial effects of HSF1 known to enhance the survival of organisms under stress come at the cost of facilitating the initiation and maintenance of cancers in mouse models and diverse human tumor lines driven by a variety of underlying oncogenic lesions. Acting at a global systems level, HSF1 function permits cells to survive the drastic imbalances in signaling and profound alterations in DNA, protein and energy metabolism that occur during malignant transformation. A novel therapeutic opportunity has been highlighted by our demonstration that knockdown of HSF1 expression using genetic techniques is well tolerated in normal cells and whole animals but that malignant cells display a profound dependence on this "non-oncogene." Relatively limited efforts have been directed so far at discovering inhibitors of this innovative target. The few HSF1 inhibitors that have been reported demonstrate limited specificity with prominent effects on general transcription and translation and poorly defined mechanisms of action. To address this deficiency and develop potent and selective inhibitors of HSF1 function, this project will join our extensive experience in the heat shock response, experimental therapeutics and cancer biology with the expertise in high-throughput screening and chemical probe optimization now available through the NIH Molecular Libraries Probe Production Center Network to accomplish the following specific aims: Aim1: Identify specific inhibitors of HSF1 using an optimized high throughput cell-based dual reporter assay that will markedly reduce false positives during the primary screening process. Aim 2: Evaluate the potency, specificity and mode of action of compounds using secondary and counter-screening assays in order to guide the selection of screen hits for analog synthesis and support their optimization into useful chemical biological probes. To validate our approach, we have completed a pilot screen with the Broad Institute Chemical Biology Platform using a collection of 70,000 known bioactive, small drug-like and purified natural products. As proof of principle, this screen identified a family of natural products that specifically inhibit the activation of HSF1. The discovery of additional inhibitors that target HSF1 function at mechanistically distinct regulatory steps in its activation will shed light on its multifaceted role in cancer biology and will provide important leads for pre- clinical studies in the chemoprevention and chemotherapy of a wide range of human cancers. PUBLIC HEALTH RELEVANCE: Heat Shock Factor 1 (HSF1) is a multifaceted and powerful regulator of tumorigenesis and malignant progression. While normal cells are not dependent upon HSF1, tumor cells are critically dependent upon it for survival. Since no specific and potent inhibitors of this innovative target exist, we propose to identify chemical probe inhibitors of HSF1 to better understand the role of HSF1 in cancer and to serve as tools in the pre- clinical development of chemopreventative and chemotherapeutic agents.

描述(申请人提供)：热休克反应(HSR)是一个强大的转录程序，作用于全基因组，不仅通过诱导热休克蛋白来恢复正常的蛋白质折叠环境，而且最近的工作表明重塑控制生存、生长和新陈代谢的全球细胞通路。在哺乳动物中，这种反应主要由热休克因子1(HSF1)调节，HSF1是一种转录因子，其作用模式在所有真核生物中都是保守的。令人惊讶的是，我们最近的工作表明，HSF1已知的许多有益作用是以促进小鼠模型和由各种潜在致癌病变驱动的各种人类肿瘤系的启动和维持为代价的。在全球系统水平上，HSF1的功能使细胞能够在恶性转化过程中发生的信号严重失衡和DNA、蛋白质和能量代谢的深刻变化中生存下来。我们的证明突显了一个新的治疗机会，即利用基因技术抑制HSF1的表达在正常细胞和整个动物中都能很好地耐受，但恶性肿瘤细胞对这种“非癌基因”表现出严重的依赖。到目前为止，在发现这一创新目标的抑制剂方面的努力相对有限。已报道的少数几种HSF1抑制剂表现出有限的特异性，对一般转录和翻译有显著影响，但作用机制尚不明确。为了解决这一不足，并开发有效和选择性的HSF1功能抑制剂，该项目将结合我们在热休克反应、实验治疗和癌症生物学方面的丰富经验，以及目前可通过NIH分子文库探针生产中心网络获得的高通量筛选和化学探针优化方面的专业知识，以实现以下具体目标：AIM1：使用优化的高通量细胞双报告基因检测来鉴定HSF1的特定抑制剂，该方法将显著减少初步筛选过程中的假阳性。目的2：用二次筛选和反筛选方法评价化合物的效价、特异性和作用方式，以指导类似物合成的筛选，并支持将其优化为有用的化学生物探针。为了验证我们的方法，我们已经完成了与博德研究所化学生物学平台的试点筛选，使用了70,000种已知的生物活性、类似小药物和纯化的天然产品的集合。作为原理的证据，这一筛选确定了一系列特定抑制HSF1激活的天然产品。更多针对HSF1功能的抑制剂的发现将揭示其在癌症生物学中的多方面作用，并将为广泛的人类癌症的化学预防和化疗的临床前研究提供重要线索。 公共卫生相关性：热休克因子1(HSF1)是肿瘤发生和恶性进展的多方面和强大的调节因子。虽然正常细胞不依赖HSF1，但肿瘤细胞严重依赖HSF1生存。由于这一创新靶点没有特异和有效的抑制剂，我们建议寻找HSF1的化学探针抑制剂，以更好地了解HSF1在癌症中的作用，并作为工具用于化学预防和化疗药物的临床前开发。