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Chemical Approaches for the Discovery of New Cancer Therapeutic Targets

发现新癌症治疗靶点的化学方法

基本信息

批准号：
7613361
负责人：
KAZUNORI KOIDE
金额：
$ 19.34万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-19 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7613361
关键词：
Antineoplastic Agents Apoptosis Binding Biological Biological Assay Biological Factors Biological Models Cancer cell line Cell physiology Cells Chemicals Collaborations DNA Damage Development Developmental Biology Drug Delivery Systems Exhibits Gene Expression Genes Goals Homeostasis Human Human Cell Line Induction of Apoptosis Label Life Malignant Neoplasms Mediating Methods Monitor Mus Normal Cell Oncogenic Pharmaceutical Preparations Pharmacologic Substance Process Proteins Radio Reporter Genes Research Research Design Signal Transduction Simian virus 40 Solid Neoplasm Specificity Structure Structure-Activity Relationship System TMC-205 Testing Transcription Factor AP-1 Transcriptional Regulation Transduction Gene Tumor Cell Line analog antineoplastic antibiotics antitumor agent base cancer therapy cellular targeting design drug development genetic regulatory protein herboxidiene insight novel novel strategies oncology professor promoter prototype therapeutic target transcription factor transcription factor Sp2 tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Background: FR901464 is a novel and potent antitumor antibiotic that exhibits prominent effects against both murine and human solid tumors. FR901464 strongly activates an SV40-driven reporter gene at low nanomolar concentrations and regulates the expression of several cancer-related genes in human cells. Despite the unique and promising biological activity of FR901464, its biological mechanisms remain to be elucidated. Objective/Hypothesis: A firm understanding of the mode of action of FR901464 will pave the way for the development of a new approach for cancer therapy. To understand the mode of action of FR901464, the target biomolecules of FR901464 need to be isolated. In this proposal, we aim to chemically synthesize FR901464 and its analogs for biological studies and use a radio-labeled FR901464 analog to isolate the target biomolecules. Specific Aims: (1) To study the chemical reactivity of FR901464 by using simple model systems; (2) to design and synthesize more stable FR901464 analogs, which will be studied in following two aims; (3) to determine the specificity of FR901464 analogs toward human tumor cell lines and normal cells and to investigate their effects on transcriptionally regulated cellular targets by high-content analysis; and (4) to isolate and characterize intracellular targets of FR901464. Study Design: First, we will study the chemical reactivities of FR901464 under biologically relevant conditions. In this study, each reactive moiety of FR901464 will be used to unambiguously analyze the results. Based on the chemical insight gained from this study, we then focus our synthetic efforts on developing stable and potent FR901464 analogs. These analogs will then be tested with various cancer cell lines to elucidate the structure-activity relationships (SAR) of FR901464. We will also perform high-content analysis to monitor various parameters (transcriptional activity, DNA damage, apoptosis, etc.). This analysis will provide more advanced insight into the specificity of FR901464 and its analogs. Finally, we will prepare radio-labeled FR901464 analogs to isolate the targets of FR901464 in live cells. Significance: The isolation of the targets of FR901464 will have significant impacts on anticancer drug development, as we envision several pharmaceutical companies will begin to look for other drugs that bind these therapeutic targets for cancer treatment.

描述（由申请人提供）：背景：FR901464 是一种新型有效的抗肿瘤抗生素，对鼠类和人类实体瘤均表现出显着的效果。 FR901464 在低纳摩尔浓度下强烈激活 SV40 驱动的报告基因，并调节人体细胞中多种癌症相关基因的表达。尽管 FR901464 具有独特且有前景的生物活性，但其生物学机制仍有待阐明。目的/假设：对 FR901464 作用模式的深入了解将为开发癌症治疗新方法铺平道路。为了了解 FR901464 的作用模式，需要分离 FR901464 的靶生物分子。在本提案中，我们的目标是化学合成FR901464及其类似物用于生物学研究，并使用放射性标记的FR901464类似物来分离目标生物分子。具体目的：（1）利用简单的模型系统研究FR901464的化学反应活性； (2)设计合成更稳定的FR901464类似物，主要围绕以下两个目标进行研究； (3) 确定FR901464类似物对人肿瘤细胞系和正常细胞的特异性，并通过高内涵分析研究其对转录调控细胞靶标的影响； (4) 分离和表征 FR901464 的细胞内靶标。研究设计：首先，我们将研究 FR901464 在生物学相关条件下的化学反应性。在本研究中，FR901464 的每个反应部分将用于明确分析结果。基于从这项研究中获得的化学见解，我们将合成工作的重点放在开发稳定且有效的 FR901464 类似物上。然后将用各种癌细胞系测试这些类似物，以阐明 FR901464 的构效关系 (SAR)。我们还将进行高内涵分析来监测各种参数（转录活性、DNA损伤、细胞凋亡等）。该分析将为 FR901464 及其类似物的特异性提供更深入的见解。最后，我们将制备放射性标记的 FR901464 类似物，以在活细胞中分离 FR901464 的靶标。意义：FR901464靶点的分离将对抗癌药物的开发产生重大影响，因为我们预计多家制药公司将开始寻找结合这些治疗靶点的其他药物来治疗癌症。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cyclic Acetal Formation Between 2-Pyridinecarboxaldehyde and gamma-Hydroxy-alpha,beta-Acetylenic Esters.

DOI：
10.1016/j.tetlet.2008.09.008
发表时间：
2008-11-10
期刊：
TETRAHEDRON LETTERS
影响因子：
1.8
作者：
Osman, Sami;Koide, Kazunori
通讯作者：
Koide, Kazunori

Ruthenium-Catalyzed Olefin Metathesis after Tetra-n-butylammonium Fluoride-Mediated Desilylation.

四正丁基氟化铵介导的脱甲硅烷基化后钌催化的烯烃复分解。

DOI：
10.1016/j.tetlet.2012.09.035
发表时间：
2012
期刊：
Tetrahedron letters
影响因子：
1.8
作者：
Osman,Sami;Koide,Kazunori
通讯作者：
Koide,Kazunori

Diastereoselective synthesis of diketopiperazine bis-α,β-epoxides.

二酮替代二哌嗪bis-α，β-环氧化物的非映选择性合成。

DOI：
10.1021/jo102096d
发表时间：
2011-02-18
期刊：
JOURNAL OF ORGANIC CHEMISTRY
影响因子：
3.6
作者：
Ando, Shin;Grote, Amy L.;Koide, Kazunori
通讯作者：
Koide, Kazunori

Structural requirements for the antiproliferative activity of pre-mRNA splicing inhibitor FR901464.

DOI：
10.1002/chem.201002402
发表时间：
2011-01-17
期刊：
CHEMISTRY-A EUROPEAN JOURNAL
影响因子：
4.3
作者：
Osman, Sami;Albert, Brian J.;Wang, Yanping;Li, Miaosheng;Czaicki, Nancy L.;Koide, Kazunori
通讯作者：
Koide, Kazunori

Development and applications of fluorogenic probes for mercury(II) based on vinyl ether oxymercuration.