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Novel Targeted Anticancer Agents from Marine Cyanobacteria

来自海洋蓝藻的新型靶向抗癌剂

基本信息

批准号：
10005117
负责人：
HENDRIK LUESCH
金额：
$ 43.91万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-06 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005117
关键词：
Antimetastatic Agent Antineoplastic Agents Bar Codes Biochemical Biological Biological Assay Breast Cancer Cell Cell Line Cells Characteristics Chemical Weapons Chemicals Collection Colorectal Cancer Coupled Cyanobacterium Cytotoxin Data Data Set Development Dolastatin 10 Drug resistance Event Florida Funding Future G-Protein-Coupled Receptors GSTP1 gene Gene Cluster Genes Genetic Growth HCT116 Cells Habitats Hawaii Histone Deacetylase Inhibitor Investigation Knowledge Laboratories Libraries Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Metagenomics Modeling Molecular Molecular Analysis Molecular Target Morphology Mus Natural Product Drug Natural Products Neoplasm Metastasis Nuclear Organism Pathway interactions Pattern Peptide Hydrolases Pharmaceutical Chemistry Phenotype Phylogenetic Analysis Planet Earth Reporter Genes Research Ribosomal RNA Sampling Source Structure Synthesis Chemistry Taxonomy Translating Validation Vascular Endothelial Growth Factors angiogenesis apratoxin base cancer cell cancer prevention cancer therapy carcinogenesis chemical synthesis colon cancer cell line cytotoxicity drug discovery efficacy study experience genetic information hypoxia inducible factor 1 in vivo inhibitor/antagonist innovation malignant breast neoplasm milligram novel novel anticancer drug novel therapeutics preservation programs prostate cancer cell rRNA Genes screening success tool transcription factor tumor xenograft

项目摘要

PROJECT SUMMARY Cyanobacteria are among the most ancient organisms on Earth and have evolved chemical weapons for defensive purposes, which we are exploiting for anticancer drug discovery. Our past research has exemplified that marine cyanobacteria produce compounds with exceptionally potent activity and/or possess unusual or first- in-class inhibitors with novel mechanisms of action. We apply a broad yet focused screening platform to maximize discovery rate of new anticancer agents. We also integrate a synthetic chemistry component into our program in order to perform rigorous biological studies to rapidly add value to our discoveries and to help solve the supply problem. Specifically, we will carry out field collections of marine cyanobacteria and prepare fraction libraries for screening in a set of innovative pathway-focused cell-based assays, utilizing various isogenic colorectal cancer cell lines and reporter gene assays, as well as newly developed unbiased phenotypic assays. We will perform dereplication, identify cyanobacteria through molecular analysis and establish phylogenetic relationships among benthic cyanobacteria. Samples will be prioritized based on bioactivity profiles and genetic uniqueness for further processing. Prioritized samples will be subjected to bioassay-guided isolation of the active compounds. Structures will be determined using NMR and mass spectrometry. Basic validation of bioactivity and secondary assays will be performed before prioritizing targets for further investigation. Selected compounds with intriguing structure and promising validated bioactivity will be targeted for total synthesis so that a rigorous biological characterization can be performed to pinpoint the molecular changes induced in the cancer cell and to determine potential direct targets. For novel noncytotoxic compounds that show potential antimetastatic activity, we will apply an orthogonal target-based screening platform.

项目总结蓝藻是地球上最古老的生物之一，它进化出了化学武器防御性目的，我们正在利用这些目的来发现抗癌药物。我们过去的研究证明了海洋蓝藻产生具有极强活性的化合物和/或具有不寻常的或第一个- 具有新作用机制的同类抑制剂。我们将广泛而专注的筛查平台应用于最大限度地提高抗癌新药的发现率。我们还将合成化学组件集成到我们的计划，以便进行严格的生物学研究，以迅速为我们的发现增加价值，并帮助解决供应问题。具体地说，我们将进行海洋蓝藻的野外采集，并制备部分文库用于在一组创新的以途径为中心的细胞分析中进行筛选，利用各种等基因结直肠癌细胞株和报告基因分析，以及新开发的无偏倚表型分析。我们将进行去复制，通过分子分析鉴定蓝藻，并建立系统发育底栖蓝藻之间的关系。样本将根据生物活性特征和遗传基因进行优先排序唯一性，便于进一步加工。按优先顺序排列的样本将接受生物测定指导下的活性物质的分离化合物。结构将使用核磁共振和质谱学来确定。生物活性的基本验证在确定进一步调查的目标的优先顺序之前，将进行二次化验。精选化合物具有耐人寻味的结构和前景被证实的生物活性将被作为全合成的目标，因此严格的可以进行生物学表征，以确定癌细胞中诱导的分子变化，并确定潜在的直接目标。对于显示潜在抗转移活性的新型非细胞毒性化合物，我们将应用基于目标的正交筛选平台。