Target ID (3 of 4)

随附的Discovery管道建议书中描述的表型筛选不能直接识别 小分子靶标，然而靶标识别对于后续的药物化学努力至关重要。 目标识别，包括治疗目标和可能导致不想要的“侧面”的“非目标” 效果“，使化合物的选择性最优化，并减少潜在的副作用 合成的毒品。目前的靶向发现和验证是药物开发的一个重大瓶颈 发现号。该方案提供了一种通过系统地使用 三种截然不同的跨学科方法。蛋白质组学、遗传学和计算方法 已在布罗德研究所制定，并将作为筛查结果的关键后续行动加以实施。 具体地说，我们将：1)开发一种系统的、蛋白质组学的方法来识别构成小分子的靶标 筛选发现；2)结合小分子和RNAi方法来识别或验证 小分子筛选发现的基础目标；以及3)开发基于以下条件的计算方法 基因表达、小分子筛选、蛋白质组学和RNAi数据以确定途径和靶点 这是小分子筛查发现的基础。目标识别的问题可能是 不是通过单一的“杀手”技术来解决问题；相反，我们设想的是多个、 互补的方法。其中的每一个都依赖于对一个问题的集中的、跨学科的努力。 仅靠一门学科的专业知识不太可能解决这一问题。 我们建议开发小分子药物，以缓解未得到满足的医疗需求。为了最大化一个 为了最大限度地减少药物的副作用，我们需要了解所有的蛋白质 (“目标”)，药物候选人将与之互动。这一提议寻求结合使用尖端技术 布罗德研究所提供了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.