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具有突出的潜力，特别是在寻求抗癌药物方面。本文将探讨largazole的构效关系，largazole是一种海洋天然产物，在体外对癌细胞具有纳米级和选择性的抗增殖活性。我们将描述抗肿瘤的作用模式，并评估最有希望的largazole类似物的治疗潜力。我们最近在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。由于HDAC活性异常导致的表观遗传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；Zolinza（默克）于2006年底被批准用于治疗皮肤t细胞淋巴瘤。经检验的工作假设是，largazole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生长，在体内可能是一种抗多种肿瘤的有效药物。首先，我们将系统地探索largazole结构中的两个领域，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largazole的I类HDAC特异性提供见解。其次，我们将研究合成的大唑类似物对各种HDAC异构体的直接影响，并评估其稳定性和代谢。第三，我们将确定用各种合成的生物活性大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。第四，我们将优先开展largazoles的药理和治疗疗效研究，并研究其在荷瘤小鼠体内的血浆稳定性和药代动力学，最终开展疗效研究。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希望的抗癌药物。我们已经从一种海洋蓝藻细菌中鉴定出一种先导化合物，我们打算合成一系列具有更高选择性和效力的相关化合物，并在癌细胞和小鼠肿瘤模型中测试最有希望的化合物的疗效。

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.