The Vanderbilt Molecular Target Discovery and Development Center

范德比尔特分子靶标发现和开发中心

• 批准号: 7853119
• 负责人: LAWRENCE J. MARNETT
• 金额: $ 220.02万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853119
• 关键词: Address; Affect; Antineoplastic Agents; Area; Arts; Binding; Biological Assay; Biology; Breast Cancer Cell; Cancer Center; Cancer cell line; Chemicals; Collaborations; Complex; Data; Data Set; Development; Drug Design; Drug resistance; Equipment; Evaluation; Explosion; Foundations; Funding; Genetic; Genomics; Goals; Grant; Hereditary Disease; Heterogeneity; Human Resources; Individual; Institutes; Investments; Knowledge; Label; Lead; Leadership; Libraries; Malignant Neoplasms; Methods; Mining; Modality; Molecular; Molecular Abnormality; Molecular Bank; Molecular Target; Mutation; Pathway interactions; Patients; Phase; Pilot Projects; Process; Proteins; RNA Interference; Reproduction spores; Research; Research Infrastructure; Resources; Screening procedure; Signal Pathway; Small Interfering RNA; Source; Staging; Structure; Technology; Testing; Therapeutic Intervention; Universities; Validation; anticancer research; base; cancer genomics; cancer therapy; drug candidate; drug development; drug discovery; efficacy testing; expectation; high throughput screening; inhibitor/antagonist; innovation; malignant breast neoplasm; malignant phenotype; meetings; novel; novel therapeutics; programs; public health relevance; quantum; small molecule; triple-negative invasive breast carcinoma; two-dimensional

DESCRIPTION (provided by applicant): Research over the past 20 years has produced an explosion of new information on the genetic changes that lead to malignancy. Yet this vast trove of knowledge has not led to a corresponding increase in new modalities for cancer therapy. This is, in part, attributable to the heterogeneity of cancer that guarantees that no single agent will be effective in all patients, and the difficulty of mining the complex genetic data to identify molecular targets and pathways that are most amenable to therapeutic intervention ("druggable"). To meet this challenge, funds are requested to create the Vanderbilt Molecular Target Discovery and Development Center (VMTDDC), an inter-institutional, multi-disciplinary collaboration between the Vanderbilt Institute of Chemical Biology (VICB) and the Vanderbilt Ingram Cancer Center (VICC). Building on the existing infrastructure and expertise of the VICB and VICC in chemical biology, drug discovery, and cancer research, the VMTDDC will establish a new paradigm for molecular target identification, validation, and development. Key to the innovative approach of the VMTDDC is the use of two-dimensional heteronuclear single quantum correlation (HSQC) NMR for molecular fragment- and structure-based drug design. This technology provides an efficient, high-throughput method to determine a potential target's druggability early in the process, thus maximizing efficiency in target selection. HSQC NMR also provides a rapid means to identify small molecules that bind to a potential target (molecular fragment leads), in addition to structural information that can be applied to rational lead optimization efforts. The VMTDDC will incorporate fragment-based drug design into an overall program of target identification and development. For the two year pilot project funding period, potential targets will be identified from aberrant signaling pathways identified through analysis of genomic data from triple negative breast cancer (TNBC), a particularly aggressive and drug resistant form of cancer. Potential targets will be validated by RNAi screening of 20 TNBC cell lines available in the VICC. Validated targets will be expressed and subjected to HSQC NMR evaluation for druggability, which also identifies molecular fragment leads. Druggable targets will be developed by a combination of fragment-based drug design and conventional high throughput screening of the VICB's 350,000 compound library, followed by structure-driven lead optimization. The ultimate goal is to identify novel, rationally selected molecular targets and to demonstrate their druggability using state-of-the-art chemical biology approaches. The VICB and VICC already possess much of the infrastructure, expertise, and leadership needed to develop the VMTDDC. The requested funding will provide the additional personnel, equipment, and material needed to allow an immediate shift of resources to a concentrated effort in the specific area of molecular target discovery and development, which will then be established as a long-term program at Vanderbilt. PUBLIC HEALTH RELEVANCE: Funds are requested to establish the Vanderbilt Molecular Target Discovery and Development Center (VMTDDC), a multi-disciplinary, inter-institutional collaboration with the aim of exploiting the wealth of cancer genomic data to identify and develop new treatment modalities for cancer. Key to the VMTDDC's innovative approach is the use of protein NMR for molecular fragment-based drug discovery, which efficiently identifies proteins that are amenable to small molecule drug development and provides critical information for lead identification and optimization. Through its combination of this ground-breaking technology with traditional drug discovery approaches, the VMTDDC will establish a new paradigm for cancer molecular target discovery and development.

描述（由申请人提供）：过去20年的研究产生了大量关于导致恶性肿瘤的遗传变化的新信息。然而，这一巨大的知识宝库并没有导致癌症治疗新模式的相应增加。这部分归因于癌症的异质性，这保证了没有单一药剂将在所有患者中有效，以及挖掘复杂的遗传数据以鉴定最适合治疗干预（“可用药”）的分子靶点和途径的困难。为了应对这一挑战，需要资金来创建范德比尔特分子靶点发现和开发中心（VMTDDC），这是范德比尔特化学生物学研究所（VICB）和范德比尔特英格拉姆癌症中心（VICC）之间的机构间多学科合作。基于VICB和VICC在化学生物学，药物发现和癌症研究方面的现有基础设施和专业知识，VMTDDC将建立分子靶点识别，验证和开发的新范式。VMTDDC创新方法的关键是使用二维异质结单量子相关（HSQC）NMR进行基于分子片段和结构的药物设计。该技术提供了一种高效、高通量的方法来在过程的早期确定潜在靶标的可药物性，从而最大限度地提高靶标选择的效率。HSQC NMR还提供了一种快速的方法来鉴定与潜在靶标结合的小分子（分子片段先导物），以及可应用于合理先导物优化工作的结构信息。 VMTDDC将把基于片段的药物设计纳入目标识别和开发的整体计划。在为期两年的试点项目资助期内，将通过分析三阴性乳腺癌（TNBC）的基因组数据，从异常信号通路中确定潜在的靶点，TNBC是一种特别具有侵袭性和耐药性的癌症。将通过对VICC中可用的20个TNBC细胞系进行RNAi筛选来验证潜在靶标。将表达经验证的靶点，并进行HSQC NMR评价，以确定药物的可药性，这也可鉴别分子片段的先导物。可药用靶点将通过基于片段的药物设计和对VICB的35万个化合物库的常规高通量筛选相结合，然后进行结构驱动的先导物优化来开发。最终目标是确定新的，合理选择的分子靶点，并使用最先进的化学生物学方法证明其可药用性。 维也纳国际中心和维也纳国际中心已经拥有发展虚拟贸易发展中心所需的大部分基础设施、专门知识和领导能力。申请的资金将提供所需的额外人员、设备和材料，以便立即将资源转移到分子靶点发现和开发的特定领域，然后将其作为范德比尔特的长期计划。 公共卫生关系：申请资金用于建立范德比尔特分子靶点发现和开发中心（VMTDDC），这是一个多学科、跨机构的合作项目，旨在利用丰富的癌症基因组数据来确定和开发新的癌症治疗模式。VMTDDC创新方法的关键是使用蛋白质NMR进行基于分子片段的药物发现，该方法可有效识别适合小分子药物开发的蛋白质，并为先导物识别和优化提供关键信息。通过将这一突破性技术与传统药物发现方法相结合，VMTDDC将为癌症分子靶点发现和开发建立新的范式。