Chemistry and Biology of Largazoles

描述（由申请人提供）：天然产物作为药物发现的起点显示出突出的潜力，特别是在寻求抗癌药物方面。本文提出的研究将探索largazole的结构-活性关系，largazole是一种海洋天然产物，在体外对癌细胞系显示出纳摩尔和选择性抗增殖活性。我们将描述抗肿瘤作用模式，并评估最有前途的largazole类似物的治疗潜力。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largazole。我们的初步数据表明，largazole是一种有效的组蛋白去乙酰化酶（HDAC）抑制剂。HDAC已经成为抗癌药物发现的有吸引力的靶标，因为由于异常HDAC活性引起的表观遗传基因沉默与几种类型的癌症相关;市场上的第一类HDAC抑制剂Zolinza（Merck）在2006年底被批准用于治疗皮肤T细胞淋巴瘤。所检验的工作假设是，largazole通过I类HDAC抑制发挥其抗肿瘤活性，从而选择性地抑制癌细胞生长，并且可能是体内针对多种肿瘤的有效药物。首先，我们将系统地探索largazole结构中的两个区域，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largazole I类HDAC特异性的见解。其次，我们将研究合成的largazole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，我们将确定用各种合成的生物活性largazoles治疗癌细胞的转录结果，并确定实现抗肿瘤活性所需的药物暴露。第四，我们将优先进行largazoles的药理学和治疗功效研究，并解决血浆稳定性，荷瘤小鼠体内药代动力学，并最终进行功效研究。公共卫生相关性：组蛋白去乙酰化酶的选择性抑制剂可能是有前途的抗癌药物。我们已经从海洋蓝藻中鉴定出一种先导化合物，我们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。

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.