Target ID

随附的Discovery Pipeline提案中描述的表型筛选并不直接识别 小分子靶点，但靶点鉴定对后续的药物化学工作至关重要。 靶点识别，包括治疗靶点和可能导致不良“副作用”的“脱靶点” 这种“副作用”使得能够优化化合物的选择性并降低化合物的副作用的可能性。 合成药物。目前实践中的靶点发现和验证是药物治疗的重要瓶颈。 的发现这一建议通过系统地使用 三种不同的跨学科方法。蛋白质组学、遗传学和计算方法学 在布罗德研究所开发，并将作为筛选结果的关键后续行动实施。 具体来说，我们将：1）开发一种系统的蛋白质组学方法来鉴定小分子基础的靶点 筛选发现; 2）结合联合收割机小分子和RNAi方法来鉴定或验证 小分子筛选发现的基础目标;以及3）开发基于 基因表达，小分子筛选，蛋白质组学和RNAi数据，以确定途径和目标 小分子筛选发现的基础目标识别问题是一个可能 不是通过单一的“杀手”技术来解决;相反，我们设想多个分析集成， 互补的方法。其中每一个都依赖于对一个问题的集中的、跨学科的努力 这不太可能单靠一门学科的专业知识就能解决。 我们建议开发小分子药物，以缓解未满足的医疗需求。为了最大限度地提高 为了提高药物的效力并最大限度地减少药物的不良副作用，我们需要了解所有的蛋白质 药物候选物将与之相互作用的靶点（“靶标”）。该提案旨在利用尖端技术和 这是布罗德研究所现有的解决目标识别难题的科学方法。

The phenotypic screens described in the accompanying Discovery Pipeline proposal do not directly identify the small-molecule target, yet target identification is vitally important to follow-up, medicinal chemistry efforts. Target identification, including both the therapeutic target and "off targets" that can result in unwanted "side effects", enables optimization of a compound's selectivity and reduction in the potential for side effects of a resultant drug. Target discovery and validation as it is currently practiced is a significant bottleneck to drug discovery. This proposal offers a solution to the target identification problem through the systematic use of three distinct and interdisciplinary approaches. Proteomic, genetic and computational methodologies have been developed at the Broad Institute and will be implemented as a critical follow-up to screening results. Specifically, we will: 1) develop a systematic, proteomic approach to identify targets that underlie smallmolecule screening discoveries; 2) combine small-molecule and RNAi methods to identify or to validate targets that underlie small-molecule screening discoveries; and 3) develop computational methods based on gene expression, small-molecule screening, and proteomic and RNAi data to identify pathways and targets that underlie small-molecule screening discoveries. The problem of target identification is one that may be solved not by a single 'killer' technology; rather, we envision the analytical integration of multiple, complementary approaches. Each of these is dependent upon a focused, interdisciplinary effort to a problem that is unlikely to be solvable with the expertise of one discipline alone. We are proposing to develop small-molecule drugs to alleviate unmet medical needs. In order to maximize a drug's potency and minimize a drug's unwanted side-effects, we need to understand all the proteins ("targets") that a drug candidate will interact with. This proposal seeks to use a combination of cutting-edge scientific approaches available at the Broad Institute to address the difficult problem of target identification.