Chemistry and Biology of Largazoles

拉格唑的化学和生物学

基本信息

批准号：
7729011
负责人：
Jiyong Hong
金额：
$ 32.74万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729011
关键词：
Active Sites Address Adenocarcinoma Cell Adverse effects Affect Antineoplastic Agents Area Binding Biological Assay Biological Factors Biology Cancer Cell Growth Cancer cell line Cell Culture Techniques Cells Chemistry Colon Adenocarcinoma Cutaneous Cyanobacterium Data Depsipeptides Detection Development Disulfides Dose Drug Exposure Drug Formulations Drug Kinetics Drug effect disorder Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epigenetic Process Gene Silencing HDAC1 gene HDAC6 gene Hela Cells High Pressure Liquid Chromatography Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Hydrolysis In Vitro Incubated Inhibition of Cancer Cell Growth Lead Lipase Marines Marketing Maximum Tolerated Dose Metabolism Methods Modeling Modification Monitor Mus Nuclear Extract Outcome Pharmaceutical Preparations Plasma Procedures Prodrugs Protein Isoforms Protocols documentation Research Schedule Series Serum Side Signal Transduction Source Specificity Staging Structure Structure-Activity Relationship T-Cell Lymphoma Testing Therapeutic Treatment Efficacy Tumor Tissue Vertebral column Work Zolinza analog antitumor drug cancer cell cancer therapy cancer type drug discovery improved in vivo inhibitor/antagonist insight marine natural product member novel potency testing preference programs public health relevance thioester tumor

项目摘要

DESCRIPTION (provided by applicant): Natural products show outstanding potential as starting point in drug discovery, especially in the quest for anticancer drugs. The research proposed here will explore structure-activity relationships of largazole, a marine natural product that shows nanomolar and selective antiproliferative activity against cancer cell lines in vitro. We will characterize the antitumor mode of action and assess the therapeutic potential of most promising largazole analogs. We recently discovered largazole during our ongoing program to find novel antitumor drugs from marine cyanobacteria. Our preliminary data indicate that largazole is a potent histone deacetylase (HDAC) inhibitor. HDACs have emerged as attractive targets for anticancer drug discovery since epigenetic gene silencing due to aberrant HDAC activity has been associated with several types of cancers; first-in-class HDAC inhibitor on the market Zolinza (Merck) was approved for the treatment of cutaneous T-cell lymphoma in late 2006. The working hypothesis tested is that largazole exerts its antitumor activity by class I HDAC inhibition, thereby selectively inhibiting cancer cell growth, and could be an effective drug against a variety of tumors in vivo. First, we will systematically explore two areas within the structure of largazole to complete our structure-activity relationship (SAR) studies, improve potency of HDAC inhibitory activity, and provide insights on the class I HDAC specificity of largazole. Second, we will examine the direct effects of synthesized largazole analogs on various HDAC isoforms and assess stability and metabolism. Third, we will determine transcriptional consequences of cancer cell treatment with various synthetic, bioactive largazoles and determine drug exposures necessary to achieve antitumor activity. Fourth, we will execute pharmacological and therapeutic efficacy studies with prioritized largazoles and address plasma stability, in vivo pharmacokinetics in tumor-bearing mice and ultimately carry out efficacy studies. PUBLIC HEALTH RELEVANCE: Selective inhibitors of the enzyme histone deacetylase could be promising anticancer agents. We have identified a lead compound from a marine cyanobacterium and we propose to synthesize a series of related compounds with improved selectivity and potency and test the efficacy of the most promising compounds in cancer cells and in mice tumor models.

描述（由申请人提供）：天然产物作为药物发现的起点显示出巨大的潜力，特别是在寻找抗癌药物方面。这里提出的研究将探索拉格唑的结构-活性关系，拉格唑是一种海洋天然产物，在体外对癌细胞系表现出纳摩尔级和选择性的抗增殖活性。我们将描述最有前途的拉格唑类似物的抗肿瘤作用模式并评估其治疗潜力。我们最近在我们正在进行的从海洋蓝藻中寻找新型抗肿瘤药物的项目中发现了拉格唑。我们的初步数据表明拉格唑是一种有效的组蛋白脱乙酰酶 (HDAC) 抑制剂。 HDAC 已成为抗癌药物发现的有吸引力的目标，因为异常 HDAC 活性导致的表观遗传基因沉默与多种类型的癌症有关。市场上一流的 HDAC 抑制剂 Zolinza（默克）于 2006 年底被批准用于治疗皮肤 T 细胞淋巴瘤。测试的工作假设是拉格唑通过 I 类 HDAC 抑制发挥其抗肿瘤活性，从而选择性抑制癌症细胞生长，并可能成为体内对抗多种肿瘤的有效药物。首先，我们将系统地探索拉格唑结构内的两个区域，以完成我们的构效关系（SAR）研究，提高 HDAC 抑制活性的效力，并提供关于拉格唑 I 类 HDAC 特异性的见解。其次，我们将检查合成的拉格唑类似物对各种 HDAC 亚型的直接影响并评估稳定性和代谢。第三，我们将确定使用各种合成的生物活性拉格唑治疗癌细胞的转录后果，并确定实现抗肿瘤活性所需的药物暴露量。第四，我们将优先开展拉格唑的药理和治疗功效研究，并解决荷瘤小鼠的血浆稳定性、体内药代动力学问题，并最终开展功效研究。公共健康相关性：组蛋白脱乙酰酶的选择性抑制剂可能是有前途的抗癌药物。我们从海洋蓝藻中鉴定出一种先导化合物，并建议合成一系列具有改进的选择性和效力的相关化合物，并测试最有前途的化合物在癌细胞和小鼠肿瘤模型中的功效。