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药物

• 批准号: 8267073
• 负责人: Eric Yiqiang Cheng
• 金额: $ 21.81万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267073
• 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; Metabolic Pathway; Mining; Molecular; National Cancer Institute; Pathway interactions; Preparation; Prodrugs; Property; Proteins; Reaction; Research; Scheme; Screening procedure; 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; microorganism; neglect; public health relevance; scaffold; small molecule; spiruchostatin A

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. PUBLIC HEALTH RELEVANCE: Selective inhibition of histone deacetylases (HDACs) has emerged as a promising avenue toward cancer therapy. We propose to discover, engineer and screen for new HDAC inhibitors with improved anticancer activities and reduced cytotoxicities. This research will generate new anticancer lead compounds for further evaluation toward clinical applications.

描述（申请人提供）：表观遗传异常参与基因突变导致癌症；因此，癌症的表观遗传干预已成为一种有希望的癌症治疗途径。小分子选择性抑制组蛋白去乙酰化酶（hdac）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。市场上第一种HDAC抑制剂Zolinza（由默克公司开发）是一种合成化合物，于2006年底被批准用于治疗皮肤t细胞淋巴瘤。FK228是一种罕见的天然产物，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，但也有一定程度的不良细胞毒性。我们对FK228和spiruchostins生物合成的研究导致了泰国depsin A和B的发现，这两种新的天然产生的FK228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）发展治疗计划（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有针对性地发现可能导致获得具有更好抗癌治疗指数的额外FK228类似物。因此，本应用的总体目标是探索自然产生和代谢工程的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fk228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、简单的基因缺失或插入、复杂的基因操作、组合生物合成、前体定向突变合成、异源寄主生物合成和工程以及化学酶合成等方法发现和构建新的FK228-家族类似物库。最后，我们将通过体外酶抑制试验和对NCI 60种癌细胞系的协同筛选，确定新的HDAC抑制剂和新的抗癌先导化合物。