NEW STRATEGIES FOR DRUG DISCOVERY: GENE EXPRESSION PROFILING AND BIOINFORMATICS

药物发现的新策略：基因表达谱分析和生物信息学

• 批准号: 6289187
• 负责人: JOHN N WEINSTEIN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 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/6289187
• 关键词: DNA topoisomerases; antiAIDS agent; antineoplastics; artificial intelligence; chemical information system; chemical kinetics; chemical models; chemical structure function; computer system design /evaluation; drug design /synthesis /production; drug screening /evaluation; electrospray ionization mass spectrometry; enzyme inhibitors; gel electrophoresis; integrase; mathematical model; matrix assisted laser desorption ionization; method development; model design /development; neoplasm /cancer pharmacology; tissue /cell culture; tumor suppressor genes

The aim of this project is to integrate three types of information on the molecular pharmacology of cancer: (1) patterns of cancer cell inhibitory activity for compounds tested in the NCIs drug discovery program; (2) molecular structural features of the tested compounds; (3) possible molecular targets and modulators of activity in the cells used for testing -- as assessed through gene and protein expression profiling. The results have implications for drug discovery and design, for possible individualization of therapy, and for clinical studies of molecular markers on cancer cells. Analytical results to date have included the following: (i) Neural networks able to predict mechanism of drug action on the basis of patterns of activity in DTPs 60-cell line cancer drug screen; (ii) A program package (DISCOVERY) that integrates information on the chemical structure, activity, and possible molecular targets of compounds tested by NCI. As the name suggests, DISCOVERY was designed to search for novel mechanisms of action among the 60,000 compounds tested to date; (iii) Neural nets and statistical methods to predict (with only moderate sensitivity and specificity, it should be stressed) the clinical activity of phase II- evaluable drugs on the basis of patterns of activity in the screen; (iv) A program package MedMiner for fluent searching of the literature on genes, drugs, and diseases to aid in expression profiling studies; (v) QSAR studies and pharmacophore searches in the NCIs DIS database for new inhibitors of HIV-1 integrase and human topoisomerase ; (vi) creation of an interface with clinical tumor specimens in the Cancer Genome Anatomy Project.Experimental results to date have included (i) Development of a large protein expression database for the 60 cell lines in the NCI drug discovery program (by 2D-gel electrophoresis, in collaboration with Dr. Leigh Anderson, Large Scale Biology Corp.); (ii) generation of a 10,000-gene mRNA expression database for the 60 cell lines using cDNA microarrays (with collaborators at Stanford University and Synteni, Inc.); (iii) generation of a 42,000-gene mRNA expression database using Affymetrix oligonucleotide chips (with collaborators at the Whitehead Genome Center); (iv) Addition to that central database of experimental data on other cell types, including endothelial cells, multi-drug resistant cancer cells, p53-isogenic cell sets, and cell types used for HIV drug discovery; (v) Development of methods based on mass spectrometry to identify and characterize proteins in the gels in sub-picomole amounts. This project as a whole represents a collaboration with the NCI Developmental Therapeutics Program, as well as a number of other laboratories. Tools and data at http://discover.nci.nih.gov. - AIDS, Cancer, Drug Discovery, gel electrophoresis, gene expression, genetic algorithm, neural network, Protein expression, microarray,

该项目的目的是整合有关癌症分子药理学的三种类型的信息：（1）NCI药物发现计划中测试的化合物的癌细胞抑制活性模式;（2）测试化合物的分子结构特征;（3）可能的分子靶点和用于测试的细胞中的活性调节剂--通过基因和蛋白质表达谱评估。这些结果对药物发现和设计、可能的个体化治疗以及癌细胞分子标记物的临床研究具有重要意义。迄今为止的分析结果包括以下内容：（i）神经网络能够根据DTP 60细胞系癌症药物筛选中的活性模式预测药物作用机制;（ii）程序包（DISCOVERY）整合了NCI测试的化合物的化学结构，活性和可能的分子靶点信息。顾名思义，DISCOVERY旨在从迄今为止测试的60，000种化合物中寻找新的作用机制;（iii）神经网络和统计方法，以预测（只有中等的敏感性和特异性，它应该强调）的临床活性的第二阶段-可评价的药物的基础上的模式的活动在屏幕上; ㈣ MedMiner程序包，用于流畅地搜索关于基因、药物和疾病的文献，以协助表达谱研究; ㈤定量构效关系研究和在国家癌症研究所DIS数据库中搜索HIV-1整合酶和人类拓扑异构酶的新抑制剂的药效团;（vi）在癌症基因组解剖学项目中建立与临床肿瘤标本的接口，迄今为止的实验结果包括（i）为NCI药物发现计划中的60种细胞系开发大型蛋白质表达数据库（通过二维凝胶电泳，与Large Scale Biology Corp.的Leigh安德森博士合作）; (ii)使用cDNA微阵列为60个细胞系生成10，000个基因mRNA表达数据库（与斯坦福大学和Synteni公司的合作者）; (iii)使用Affytron寡核苷酸芯片生成42，000个基因mRNA表达数据库（与Whitehead基因组中心的合作者）;（iv）在该中央数据库中增加关于其他细胞类型的实验数据，包括内皮细胞、多药耐药癌细胞、p53等基因细胞集和用于HIV药物发现的细胞类型; ㈤开发基于质谱法的方法，以确定和表征凝胶中亚皮摩尔量的蛋白质。该项目作为一个整体代表了与NCI发展治疗计划以及其他一些实验室的合作。工具和数据http://discover.nci.nih.gov. -艾滋病，癌症，药物发现，凝胶电泳，基因表达，遗传算法，神经网络，蛋白质表达，微阵列，