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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：
10738315
负责人：
HENDRIK LUESCH
金额：
$ 4.43万
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/10738315
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 Dimensions 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 Learning Libraries Malignant Neoplasms Malignant neoplasm of pancreas Mass Spectrum Analysis Metagenomics Microtubules 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 cancer cell cancer drug resistance 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 innovation malignant breast neoplasm marine milligram novel novel anticancer drug novel therapeutics preservation programs prostate cancer cell rRNA Genes screening secondary metabolite 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

项目成果

期刊论文数量（71）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria.

DOI：
10.1002/chem.201600674
发表时间：
2016-06-06
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
0
作者：
Gunasekera SP;Li Y;Ratnayake R;Luo D;Lo J;Reibenspies JH;Xu Z;Clare-Salzler MJ;Ye T;Paul VJ;Luesch H
通讯作者：
Luesch H

A Complementary Chemical and Genomic Screening Approach for Druggable Targets in the Nrf2 Pathway and Small Molecule Inhibitors to Overcome Cancer Cell Drug Resistance.