Chemistry and Biology of Largazoles

描述(申请人提供)：天然产物在药物发现，特别是在寻找抗癌药物方面显示出突出的潜力。这项研究将探索海洋天然产物大黄唑的构效关系。大黄唑是一种海洋天然产物，在体外显示出纳米分子和选择性的抗癌细胞活性。我们将描述抗肿瘤的作用模式，并评估最有希望的精灵类似物的治疗潜力。我们最近在我们正在进行的从海洋蓝藻中寻找新的抗肿瘤药物的计划中发现了精灵。我们的初步数据表明，精灵是一种有效的组蛋白脱乙酰酶(HDAC)抑制剂。由于HDAC活性异常引起的表观基因沉默与几种类型的癌症有关，HDAC已成为抗癌药物发现的有吸引力的靶点；市场上的第一类HDAC抑制剂佐林扎(Merck)于2006年底被批准用于治疗皮肤T细胞淋巴瘤。验证的工作假说是，精胺唑通过抑制I类HDAC发挥其抗肿瘤活性，从而选择性地抑制癌细胞的生长，在体内可能是一种有效的抗肿瘤药物。首先，我们将系统地探索精唑结构中的两个区域，以完成我们的构效关系(SAR)研究，提高HDAC抑制活性的效力，并对精唑的I类HDAC专一性提供见解。其次，我们将研究合成的精唑类似物对各种HDAC亚型的直接影响，并评估稳定性和新陈代谢。第三，我们将确定用各种合成的、生物活性的大氮唑治疗癌细胞的转录后果，并确定实现抗肿瘤活性所必需的药物暴露。第四，我们将优先开展大氮唑类药物的药理和治疗疗效研究，解决荷瘤小鼠的血浆稳定性、体内药代动力学问题，并最终开展疗效研究。与公众健康相关：组蛋白脱乙酰酶的选择性抑制剂可能是很有前途的抗癌药物。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更高选择性和有效性的相关化合物，并测试最有希望的化合物在癌细胞和小鼠肿瘤模型中的有效性。

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.