The Vanderbilt Molecular Target Discovery and Development Center

描述(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基因变化的新信息。然而，这一巨大的知识宝库并没有导致癌症治疗新方法的相应增加。这在一定程度上是由于癌症的异质性，这保证了没有一种单一的药物对所有患者都有效，而且很难挖掘复杂的遗传数据来确定最适合治疗干预的分子靶点和途径(“可用药”)。为了迎接这一挑战，需要资金来创建范德比尔特分子靶标发现和开发中心(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)之间的跨机构、多学科合作。在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的基础上，VMTDDC将建立分子靶标识别、验证和开发的新范式。VMTDDC创新方法的关键是使用二维异核单量子相关(HSQC)核磁共振进行基于分子片段和结构的药物设计。这项技术提供了一种高效、高通量的方法，可以在过程的早期确定潜在目标的可药性，从而最大限度地提高目标选择的效率。HSQC核磁共振还提供了一种快速识别与潜在目标(分子片段导联)结合的小分子的方法，以及可应用于合理导联优化工作的结构信息。 VMTDDC将把基于片段的药物设计纳入靶标识别和开发的整体计划。在两年的试点项目资助期内，将从通过分析三阴性乳腺癌(TNBC)的基因组数据确定的异常信号通路中确定潜在的靶点。三阴性乳腺癌是一种特别具有侵袭性和抗药性的癌症。潜在的靶点将通过对VICC中可用的20个TNBC细胞株进行RNAi筛选来验证。验证的靶标将被表达并接受HSQC核磁共振药剂性评估，这也识别分子片段前导。可药物靶标的开发将结合基于片段的药物设计和对VICB的350,000个化合物文库的传统高通量筛选，然后是结构驱动的先导优化。最终目标是识别新的、合理选择的分子靶标，并使用最先进的化学生物学方法证明它们的可药性。 VICB和VICC已经拥有发展VMTDDC所需的大部分基础设施、专业知识和领导力。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标发现和开发的特定领域，然后作为范德比尔特的长期计划建立起来。 公共卫生意义：需要资金建立范德比尔特分子靶标发现和开发中心(VMTDDC)，这是一个多学科、机构间的合作，目的是利用丰富的癌症基因组数据来确定和开发癌症的新治疗方式。VMTDDC创新方法的关键是将蛋白质核磁共振用于基于分子片段的药物发现，这种方法有效地识别了服从小分子药物开发的蛋白质，并为铅的识别和优化提供了关键信息。通过将这一突破性技术与传统药物发现方法相结合，VMTDDC将为癌症分子靶标的发现和开发建立一个新的范例。

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.