Probes, Inhibitors, and PROTACs (PIP) Core

项目摘要：探测器、抑制剂和PROTAC(PIP)核心 PIP核心的首要任务是使用复杂的化学和质谱学来 开发小分子，促进分子靶标的发现和开发。遗传方法 通常用于识别、开发和验证分子靶标。这些方法依赖于改变DNA 或蛋白质靶标的RNA序列。然而，药物发现依赖于操纵 相应的蛋白质使用小分子。通常情况下，通过这些互补的方式获得的结果 策略不相关。1与这些正交方法的结果相关的不一致性 可以归因于依赖于多种功能的复杂的生物学，即酶和支架， 与蛋白质靶标相关联。通过改变核酸来调节蛋白质水平可以消除所有靶标 蛋白质的功能。然而，小分子调节剂可以被调节来诱导任一特定的区域效应 (可逆或不可逆)或去除整个蛋白质(PROTAC)，并进行精确的时间控制。这些 可以用可光激活或荧光分子或生物素标记，以实现目标识别和 验证，研究作用机制，或描述相关的互动组。除了设计和 合成上述类型的小分子，PIP Core还将为以下对象提供放大服务(mg到g 其他实验，如体内目标验证和命中到领先的优化研究，以生成 结构活性关系(SAR)数据。将使用质谱学来表征这些影响 蛋白质组上的化合物通过蛋白质和翻译后或化学的定量分析 修改以验证可能导致耐药性的作用机制和代偿特征。 核心将由Natarajan博士和伍兹博士领导，他们将为PIP核心带来互补的专业知识。Dr。 Natarajan在开发探针、抑制剂和ProTAC方面拥有广泛的专业知识，使用尖端化学 方法：研究方法。伍兹博士拥有丰富的经验，将质谱学作为描绘蛋白质的平台-- 蛋白质相互作用、翻译后修饰和癌症治疗反应的多变量生物标记物。 CMTDD研究项目负责人、CMTDD成员将广泛使用PIP核心服务 以及大学的研究人员。

Project Summary: Probes, Inhibitors, and PROTACs (PIP) Core The overarching mission of the PIP Core is to use sophisticated chemistry and mass spectrometry for development of small molecules that facilitate molecular target discovery and development. Genetic methods are routinely used to identify, develop, and validate molecular targets. These methods rely on altering the DNA or RNA sequences of the protein target. However, drug discovery relies on manipulating the function of the corresponding proteins using small molecules. Often the results obtained through these complementary strategies do not correlate.1 The incongruence associated with the results from these orthogonal approaches can be attributed to the complex biology that is dependent on multiple functions i.e., enzymatic and scaffolding, associated with the protein target. Modulating protein levels by altering the nucleic acids eliminates all the target protein functions. However small molecule modulators can be tuned to induce either domain specific effects (reversible or irreversible) or removal of the entire protein (PROTAC) with exquisite temporal control. These could be tagged with photoactivatable or fluorescent molecules, or biotin to enable target identification and validation, study mechanism of action, or characterize the associated interactome. In addition to the design and synthesis of above types of small molecules, the PIP Core will also provide scale up services (mg to g) for additional experiments such as in vivo validation of targets and hit-to-lead optimization studies to generate structure activity relationship (SAR) data. Mass spectrometry will be used to characterize the impact of these compounds on the proteome through quantitative analysis of proteins and posttranslational or chemical modifications to validate mechanism of action and compensatory features that may contribute to drug resistance. The Core will be led by Drs. Natarajan and Woods, who will bring complementary expertise to the PIP Core. Dr. Natarajan has extensive expertise in developing probes, inhibitors, and PROTACs, using cutting edge chemistry methods. Dr. Woods has extensive experience using mass spectrometry as a platform for delineating protein- protein interactions, posttranslational modifications, and multivariate biomarkers of cancer response to therapy. PIP Core services will be extensively utilized by CMTDD Research Project Leaders (RPLs), CMTDD members and University researchers at large.