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Discover and Engineer New Histone Deacetylase Inhibitors as Anticancer Agents

发现并设计新的组蛋白脱乙酰酶抑制剂作为抗癌剂

基本信息

批准号：
8734896
负责人：
Eric Yiqiang Cheng
金额：
$ 20.64万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8734896
关键词：
Address Anabolism Anti-Bacterial Agents Antineoplastic Agents Apoptosis Bacteria Biochemical Reaction Biological Assay Biological Factors Cancer Etiology Cancer Intervention Cancer cell line Characteristics Chemicals Clinical Clinical Trials Cloning Complex Cutaneous Developmental Therapeutics Program Engineering Enzyme Inhibition Enzymes Epigenetic Process Evaluation Family Fermentation Gene Cluster Gene Deletion Gene Mutation Genes Genetic Genome Goals Gram-Negative Bacteria Histone Deacetylase Inhibitor Histones In Vitro Lead Libraries Mammalian Cell Marketing Mediating Metabolic Pathway Mining Molecular National Cancer Institute Pathway interactions Preparation Prodrugs Property Proteins Reaction Research Scheme Source Staging Structure Substrate Specificity Sulfhydryl Compounds T-Cell Lymphoma Therapeutic Index Tumor Suppressor Genes United States Food and Drug Administration Vorinostat Work Zolinza analog anti-cancer therapeutic anticancer activity base cancer regression cancer therapy chromatin remodeling clinical application combinatorial cytotoxicity disulfide bond drug development flexibility genetic manipulation improved in vivo indexing inhibitor/antagonist metabolic engineering microorganism neglect public health relevance scaffold screening small molecule spiruchostatin A

项目摘要

DESCRIPTION (provided by applicant): Epigenetic abnormalities participate with genetic mutations to cause cancer; consequently epigenetic intervention of cancer has emerged as a promising avenue toward cancer therapy. Selective inhibition of histone deacetylases (HDACs) by small molecules often leads to a cascade of chromatin remodeling, tumor suppressor gene reactivation, apoptosis, and regression of cancer. First-in-class HDAC inhibitor on the market, Zolinza (by Merck) - a synthetic compound, was approved for the treatment of cutaneous T-cell lymphoma in late 2006. FK228 represents a small family of rare natural products with unique structural properties, potent HDAC inhibition activities, good anticancer therapeutic index, but also certain levels of undesirable cytotoxicity. Our studies of the biosynthesis of FK228 and spiruchostatins have led to the discovery of thailandepsins A and B, two new naturally produced FK228-family analogs with better HDAC inhibition activities and predicted anticancer activities currently being evaluated at the US National Cancer Institute (NCI) Developmental Therapeutics Program (DTP). Our working hypothesis is that targeted discovery from prioritized microorganisms and biosynthetic engineering of parallel metabolic pathways could lead to the acquisition of additional FK228 analogs with better anticancer therapeutic index. Thus, the overall goal of this application is to explore naturally produced and metabolically engineered HDAC inhibitors as anticancer lead compounds. To achieve this goal we will pursue the following studies: Firstly, we will characterize new genes and new pathways involved in the biosynthesis of FK228-family natural products in selected bacterial species. This study will provide important guidance for downstream engineered biosynthesis efforts. Secondly, we will discover and engineer a library of new FK228- family analogs by means of targeted bioprospecting, genome mining, simple gene deletion or insertion, complex genetic manipulation, combinatorial biosynthesis, precursor-directed mutasynthesis, de novo biosynthesis and engineering in heterologous hosts, and chemoenzymatic synthesis. Finally, we will identify new HDAC inhibitors and new anticancer lead compounds through in vitro enzyme inhibition assays and collaborative screening against the NCI's 60 cancer cell lines.

描述（由申请人提供）：表观遗传异常与基因突变一起导致癌症;因此，癌症的表观遗传干预已成为癌症治疗的一种有前途的途径。小分子对组蛋白脱乙酰酶（HDAC）的选择性抑制通常会导致染色质重塑、肿瘤抑制基因再激活、细胞凋亡和癌症消退的级联反应。市场上的第一类HDAC抑制剂Zolinza（Merck）-一种合成化合物，于2006年底被批准用于治疗皮肤T细胞淋巴瘤。FK 228代表了一个小家族的稀有天然产物，具有独特的结构特性，有效的HDAC抑制活性，良好的抗癌治疗指数，但也有一定水平的不良细胞毒性。我们对FK 228和螺环内酯生物合成的研究发现了thailandepsins A和B，这两种新的天然产生的FK 228家族类似物具有更好的HDAC抑制活性和预测的抗癌活性，目前正在美国国家癌症研究所（NCI）发育治疗计划（DTP）中进行评估。我们的工作假设是，从优先微生物和平行代谢途径的生物合成工程中靶向发现可能导致获得具有更好抗癌治疗指数的其他FK 228类似物。因此，本申请的总体目标是探索天然产生和代谢工程改造的HDAC抑制剂作为抗癌先导化合物。为了实现这一目标，我们将进行以下研究：首先，我们将在选定的细菌物种中表征参与FK 228家族天然产物生物合成的新基因和新途径。该研究将为下游工程生物合成工作提供重要指导。其次，我们将通过靶向生物勘探、基因组挖掘、简单基因缺失或插入、复杂遗传操作、组合生物合成、突变体定向突变合成、异源宿主中的从头生物合成和工程以及化学酶合成来发现和工程化新的FK 228家族类似物库。最后，我们将通过体外酶抑制试验和针对NCI的60种癌细胞系的协作筛选来鉴定新的HDAC抑制剂和新的抗癌先导化合物。