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）：天然产品在药物发现的起点上表现出杰出的潜力，尤其是在寻求抗癌药物方面。此处提出的研究将探索大拉唑的结构活性关系，这是一种海洋天然产物，在体外显示了针对癌细胞系的纳摩尔和选择性抗增殖活性。我们将表征抗肿瘤的作用方式，并评估最有前途的大量类似物的治疗潜力。最近，我们在正在进行的计划中发现了大拉唑，以从海洋蓝细菌中找到新型抗肿瘤药物。我们的初步数据表明，大拉唑是一种有效的组蛋白脱乙酰基酶（HDAC）抑制剂。由于异常HDAC活性引起的表观遗传基因沉默与几种类型的癌症有关，因此HDAC已成为抗癌药物发现的有吸引力的靶标。市场Zolinza（Merck）上的第一类HDAC抑制剂在2006年末被批准用于治疗皮肤T细胞淋巴瘤。进行的工作假设是，Largazole通过I类HDAC抑制作用施加其抗肿瘤活性，从而选择性地抑制癌细胞的生长，并且可以有效地抗药药物，从而有效地抗药性药物。首先，我们将系统地探索大拉戈唑结构内的两个领域，以完成我们的结构活性关系（SAR）研究，提高HDAC抑制活性的效力，并提供有关大兰加唑I类特异性的见解。其次，我们将研究合成的大左右类似物对各种HDAC同工型的直接影响，并评估稳定性和代谢。第三，我们将确定各种合成，生物活性大量的癌细胞处理的转录后果，并确定获得抗肿瘤活性所需的药物暴露。第四，我们将通过优先级别的大左右执行药理和治疗功效研究，并解决血浆稳定性，在承重肿瘤小鼠的体内药代动力学，并最终进行疗效研究。公共卫生相关性：酶组蛋白脱乙酰基酶的选择性抑制剂可能是有希望的抗癌剂。我们已经从海洋蓝细菌中鉴定出铅化合物，并提议合成一系列具有提高选择性和效力的相关化合物，并测试癌细胞和小鼠肿瘤模型中最有希望的化合物的功效。