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Establishing a molecular system for drug targeting of transcriptional control

建立转录控制药物靶向分子系统

基本信息

批准号：
8118451
负责人：
LAURENCE H. HURLEY
金额：
$ 29.7万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): We have identified a new class of molecular receptors amenable to drug targeting to modulate gene expression. Modulation of gene expression has broad applications in molecular therapeutics, including cancer, heart disease, inflammation, neurodegeneration, endocrinology, asthma, and diabetes. The scientific community affected by this discovery is very broad and includes basic as well as translational scientists. These molecular targets comprise secondary DNA structures (G- quadruplexes and i-motifs) found frequently in the promoter elements of a wide variety of genes including c-Myc, Bcl-2, VEGF, Hif-1a, PDGF-A, and RET. Proof of principle exists that stabilization of these secondary DNA structures with small molecules results in repression of gene expression in cells and this repression is dependent on an intact G-quadruplex in the promoter region. Quarfloxin, a drug originating from the PI's laboratory, is a first-in-class G-quadruplex-interactive drug that targets G-quadruplexes in ribosomal DNA and is in phase II clinical trials. The selectivity and corresponding lack of any serious toxicity in the clinical trials is partially dependent on the selective uptake into the nucleolus of cancer cells along with the 400-fold selectivity of Quarfloxin for the parallel-type G-quadruplex found in rDNA over duplex DNA. The objective of this proposal is to provide structural insight into silencer elements consisting of a G- quadruplex and i-motif within a duplex region that corresponds to the silencer elements. Herein lies the challenge because the i-motif is only normally generated under the negative superhelicity found in a plasmid supercoiled state or as a consequence of transcriptional runoff. We have proposed a solution to this problem along with techniques to provide a structure-based approach and development of a high-throughput assay for screening for compounds that interact with this composite structure. The ability to form the composite i-motif/G-quadruplex structure within a duplex molecule will permit us to identify small molecules that have enhanced target selectivity. The challenge addressed in this proposal is to design a system in which we can externally control the production of genes in cells. This technology, if successful, will have applications in the treatment of cancer, heart disease, and Alzheimer's disease.

描述（由申请人提供）：我们已经鉴定了一类新的分子受体，其适于药物靶向以调节基因表达。基因表达的调节在分子治疗中具有广泛的应用，包括癌症、心脏病、炎症、神经变性、内分泌学、哮喘和糖尿病。受这一发现影响的科学界非常广泛，包括基础科学家和转化科学家。这些分子靶标包括二级DNA结构（G-四链体和i-基序），其经常在包括c-Myc、Bcl-2、VEGF、Hif-1a、PDGF-A和RET在内的多种基因的启动子元件中发现。存在的原理证明，这些二级DNA结构与小分子的稳定化导致细胞中基因表达的抑制，并且这种抑制依赖于启动子区域中的完整G-四链体。Quarfloxin是一种来自PI实验室的药物，是一种一流的G-四链体相互作用药物，靶向核糖体DNA中的G-四链体，并处于II期临床试验中。临床试验中的选择性和相应的任何严重毒性的缺乏部分地取决于选择性摄取到癌细胞的核仁中沿着Quarfloxin对rDNA中发现的平行型G-四链体的400倍选择性超过双链体DNA。该提议的目的是提供对由对应于沉默元件的双链体区域内的G-四链体和i-基序组成的沉默元件的结构洞察。这里存在挑战，因为i基序通常仅在质粒超螺旋状态中发现的负超螺旋性下或作为转录径流的结果产生。我们已经提出了一个解决这个问题的方法，沿着与技术，以提供一个基于结构的方法和开发的高通量检测筛选与这种复合结构的化合物。在双链体分子内形成复合i-基序/G-四链体结构的能力将允许我们鉴定具有增强的靶选择性的小分子。这项提案所面临的挑战是设计一个系统，在这个系统中，我们可以从外部控制细胞中基因的产生。这项技术如果成功，将应用于治疗癌症，心脏病和阿尔茨海默病。