DRUG TARGETING OF G-QUADRAPLEX-NM23-H2 COMPLEX IN THE c-MYC PROMOTER

c-MYC 启动子中 G-QUADRAPLEX-NM23-H2 复合物的药物靶向

基本信息

批准号：
7600489
负责人：
LAURENCE H. HURLEY
金额：
$ 34.25万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7600489
关键词：
Affinity Arizona Back Binding Binding Sites Biochemical Biological Assay Biological Models Cell Line Cells Chemicals Class Clinical Clinical Trials Collaborations Colon Carcinoma Colorectal Cancer Complex Computer Assisted Databases Development Development Plans Docking Drug Delivery Systems Drug Design Drug Interactions Elements Engineering Environment Evaluation Event Fluorescence Resonance Energy Transfer Fluoroquinolones G-Quartets Gene Expression Genetic Polymorphism Genetic Transcription Goals Grant Heterogeneous-Nuclear Ribonucleoprotein K Human Hypersensitivity Image Immunohistochemistry In Vitro Induction of Apoptosis Lead Luciferases Malignant neoplasm of pancreas Mediating Methods Modeling Molecular Target Molecular Weight New Agents Patient Selection Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Positioning Attribute Preparation Principal Investigator Program Development Progress Reports Property Reproduction spores Research Screening procedure Structure System Techniques Testing Transcriptional Activation Transcriptional Regulation Transcriptional Silencer Elements Universities Work Yang antitumor agent base c-myc Genes cancer cell concept design experience fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether high throughput screening in vivo inhibitor/antagonist innovation insight molecular modeling mouse model novel nuclease pharmacophore pre-clinical prevent programs promoter small molecule small molecule libraries tetra(4-N-methylpyridyl)porphine tumor virtual

项目摘要

The translational goal in Project 4 is to identify and bring forward into clinical trials one or two lead compounds that will suppress c-Myc transcription by targeting the NM23-H2-DNA complex. This proposal builds upon progress from the last grant period and will further test hypothesis that the NM23-H2-DNA complex is critically involved in transcriptional activation of c-Myc and c-Myc is a critical factor in colon cancer. The specific aims of the proposal are (1) structural characterization of the G-quadruplex-drug complexes in the c-Myc promoter, (2) to establish in vitro biochemical and cell-based screens to identify small molecules that inhibit binding of NM23-H2 to the G-quadruplex in the silencer element of the c-Myc promoter, (3) to discover and optimize G-quadruplex- and NM23-H2-interactive compounds using computer- aided drug design and structure-based and virtual-screening approaches, (4) In vivo evaluation and subsequent preclinical development, and (5) to file an IND for Phase I clinical trial and overall clinical development program. High-field NMR will be used to characterize the drug-G-quadruplex complex, molecular modeling will be used to identify new lead compounds, and fluorescence resonance energy transfer (FRET) and double-filter methods will be used for identification of in vitro biochemical hits. A luciferase-based high-throughput screen has already been used to identify hits, and subsequent assays will be carried out in matched cell lines genetically engineered to provide proof of principle that the mechanism of action is as proposed. Structure-based approaches will be used to aid in lead optimization. Following lead optimization, an IND will be filed and the clinical development program will be based upon discoveries from specific aims 1-4. Immunohistochemistry will be used to guide patient selection and phase I and II clinical trial plans will be designed to determine whether the new agents will help patients with advanced colorectal cancer. The long-term goal of this research is to develop novel target-directed drugs for treatment of colorectal cancer.

项目4中的翻译目标是识别并提出临床试验一两个领导通过靶向NM23-H2-DNA复合物来抑制C-MYC转录的化合物。该提议以最后一个赠款期的进展为基础，并将进一步检验 NM23-H2-DNA复合物与C-Myc的转录激活至关重要，C-MYC是关键结肠癌的因素。该提案的具体目的是（1）G-四链体毒物复合物的结构表征在C-MYC启动子中，（2）建立体外生化和基于细胞的筛选以识别小抑制NM23-H2与C-Myc的消音器元件中G-四链体结合的分子启动子（3）使用计算机 - 辅助药物设计和基于结构和虚拟筛查方法，（4）体内评估和随后的临床前开发，（5）为I期临床试验和整体临床提交IND 发展计划。高视野NMR将用于表征药物 - 二链体络合物，分子建模将用于鉴定新的铅化合物和荧光共振能转移（FRET）和双过滤器方法将用于识别体外生化命中。一个基于荧光素酶的高通量屏幕已经用于识别命中，随后的测定将在基因工程的匹配细胞系中进行，以提供原理证明机制行动是指的。基于结构的方法将用于帮助铅优化。下列的铅优化，将提交IND，临床开发计划将基于发现从特定的目标1-4。免疫组织化学将用于指导患者选择以及I和II期临床试验计划将旨在确定新代理人是否会帮助患者结直肠癌。这项研究的长期目标是开发新型目标定向药物以治疗结直肠癌症。