A Chemical Biology Approach for Discovery of HDAC Inhibitors

发现 HDAC 抑制剂的化学生物学方法

• 批准号: 7941595
• 负责人: TARO AMAGATA
• 金额: $ 14.55万
• 依托单位: SAN FRANCISCO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941595
• 关键词: Actinobacteria class; Actinomyces; Antineoplastic Agents; Area; Attention; Biological Assay; Biological Factors; Biological Markers; Biological Process; Biology; Boxing; Camptothecin; Chemicals; Chromatin; Clinical Trials; Communities; Crude Extracts; DNA Sequence; Development; Disease; Environment; Enzymes; Epigenetic Process; Gene Expression; Genetic Transcription; Goals; Healthcare; High Pressure Liquid Chromatography; Histone Deacetylase Inhibitor; Histones; Human; Laboratories; Libraries; Lysine; Malignant Neoplasms; Marines; Mentors; Mentorship; Mitotic Checkpoint; Modification; Natural Products Chemistry; Outcome; Paclitaxel; Protein Isoforms; Public Health; Recruitment Activity; Research; Research Project Grants; Research Proposals; Saccharomyces; Saccharomycetales; San Francisco; Scientist; Screening procedure; Sirtuins; Source; Students; TP53 gene; Training; Tubulin; Tumor Suppressor Genes; Work; Yeasts; angiogenesis; authority; cancer cell; career; career development; drug development; inhibitor/antagonist; innovation; marine natural product; microorganism; novel; professor; public health relevance; sample collection; skills; small molecule; small molecule libraries; tumorigenesis; verdin photosensitizer

DESCRIPTION (provided by applicant): Epigenetic alterations (i.e. that do not involve changes in the underlying DNA sequence) of chromatin are known to cause gene transcription and gene expression disorders connected to tumorigenesis. Histone deacetylases (HDACs), a group of epigenetic enzymes that modulate chromatin activity by removing acetyl groups from the lysine residues of histones, have received worldwide attention as anticancer targeted molecules. Specifically, class III HDACs (SIRT1 - 7) have emerged as one of the most important cancer targeted molecules. Notably, SIRT 1 and 2 are expected to be potential biomarkers for tumorigenesis since they are proven to be over-expressed in cancer cells. SIRT1 regulates several tumor suppressor genes such as p53 and forkhead box (FOXO) whereas SIRT2 regulates a G2/M mitotic checkpoint and 1-tubulin stability. Interestingly, all the HDAC inhibitors currently being evaluated as anticancer drugs in clinical trials act as either class I specific or class I and II non-specific inhibitors. Since SIRTs possess the same biological functions as classical HDACs, SIRT inhibitors have great potential to be anticancer leads with a new mode of action. Despite clear evidence that SIRTs are anticancer targeted molecules, development of SIRT inhibitors is especially lacking when compared with that of classical HDAC inhibitors. Furthermore, no SIRT inhibitors have been evaluated as anticancer leads in clinical trials. This research proposal is an innovative approach to discover class III specific HDAC inhibitors from rare marine-derived actinomycetes. The specific aims of this research plans are as follows: (1) Create crude extract libraries and highly fractionated HPLC peak libraries from rare marine-derived actinomycetes. (2) Identify and characterize novel Sir2 inhibitors using a yeast assay. (3) Apply a SIRT enzyme assay to chemical libraries and pure compounds. PUBLIC HEALTH RELEVANCE: Relevance to public health the development of isoform-specific HDAC inhibitors is an exciting approach for the discovery of novel anticancer drugs. Class III HDAC inhibitors are promising anticancer leads with a new mode of action. The expected outcome will directly contribute to human healthcare by offering new treatment option against cancer.

描述（由申请人提供）：已知染色质的表观遗传学改变（即不涉及基础DNA序列的变化）会导致与肿瘤发生有关的基因转录和基因表达障碍。组蛋白脱乙酰基酶（HDACS）是一组表观遗传酶，通过去除组蛋白的赖氨酸残基来调节染色质活性，已作为抗癌靶向分子而受到全世界的关注。具体而言，III类HDAC（SIRT1-7）已成为最重要的癌症分子之一。值得注意的是，SIRT 1和2有望成为肿瘤发生的潜在生物标志物，因为事实证明它们在癌细胞中被过表达。 SIRT1调节几个肿瘤抑制基因，例如p53和叉子盒（FoxO），而SIRT2调节G2/M有丝分裂检查点和1-微管蛋白的稳定性。有趣的是，目前在临床试验中被评估为抗癌药物的所有HDAC抑制剂作为I类特异性或I类和II类非特异性抑制剂。由于SIRT具有与经典HDAC相同的生物学功能，因此SIRT抑制剂具有具有新的作用方式的抗癌导线的巨大潜力。尽管有明确的证据表明SIRT是抗癌靶向分子，但与经典的HDAC抑制剂相比，SIRT抑制剂的发展尤其缺乏。此外，在临床试验中，没有评估任何SIRT抑制剂作为抗癌导线。该研究建议是一种创新的方法，可以从稀有海洋衍生的放线菌发现III类特异性HDAC抑制剂。该研究计划的具体目的如下：（1）从稀有的海洋衍生的放线菌创建原始提取物库和高度分馏的HPLC峰文库。 （2）使用酵母测定法确定并表征新型SIR2抑制剂。 （3）将SIRT酶测定法应用于化学文库和纯化合物。 公共卫生相关性：与公共卫生相关的同工型特异性HDAC抑制剂的开发是发现新型抗癌药物的一种令人兴奋的方法。 III类HDAC抑制剂是具有新的作用方式的有前途的抗癌导线。预期的结果将通过提供针对癌症的新治疗选择直接促进人类医疗保健。