Probes, Inhibitors, and PROTACs (PIP) Core

探针、抑制剂和 PROTAC (PIP) 核心

• 批准号: 10714240
• 负责人: Amarnath Natarajan
• 金额: $ 18.58万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-16 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714240
• 关键词: Address; Adrenal Glands; Alkynes; Alleles; Amino Acid Sequence; Binding; Binding Sites; Biological; Biology; Biotin; Biotinylation; CDK4 gene; CDK5 gene; Cells; Centers of Research Excellence; Chemicals; Chemistry; Colorectal Cancer; Communities; Complex; Coupled; DNA Sequence; DNA lesion; Data; Development; Drug Targeting; Drug resistance; Environment; Evaluation; Excision; Experimental Genetics; FDA approved; Faculty Recruitment; Funding; Future; Genetic; Genetic Code; Glycolysis; Grant; Kinetics; Legal patent; Libraries; Lysine; Maps; Mass Spectrum Analysis; Methods; Mission; Modification; Molecular; Molecular Target; Mutate; Nebraska; Neurologic; Nucleic Acids; Organoids; Pathway Analysis; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Protac; Protein Analysis; Proteins; Proteome; Proteomics; Publications; RNA Sequences; Recombinant Proteins; Regulation; Research; Research Personnel; Research Project Grants; Role; Scientist; Services; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Structure; Structure-Activity Relationship; System; T-Lymphocyte; Technology; Therapeutic; Time; Tissues; Ubiquitin; Universities; Validation; analog; assay development; cancer biomarkers; chemical genetics; chemical synthesis; design; differential expression; drug discovery; experience; experimental study; functional group; in vivo; inhibitor; instrumentation; interest; lead optimization; medullary thyroid carcinoma; member; multicatalytic endopeptidase complex; neuroendocrine cancer; neuropsychiatry; novel; p53-binding protein 1; pre-clinical; programs; protein degradation; protein function; protein protein interaction; recruit; resistance mechanism; scaffold; scale up; small molecule; small molecule libraries; spatiotemporal; therapeutic development; therapeutic target; tool; treatment response; ubiquitin-protein ligase

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.

项目概要：探针、抑制剂和PROTAC（PIP）核心 PIP核心的首要使命是使用复杂的化学和质谱法， 促进分子靶标发现和开发的小分子的开发。遗传方法 常规用于鉴定、开发和验证分子靶标。这些方法依赖于改变DNA 或蛋白质靶的RNA序列。然而，药物发现依赖于操纵的功能， 用小分子合成相应的蛋白质通过这些互补的方法获得的结果往往 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生物学，即，酶和支架， 与蛋白质靶点相关。通过改变核酸来调节蛋白质水平， 蛋白质功能然而，小分子调节剂可以被调节以诱导结构域特异性效应， （可逆或不可逆）或以精确的时间控制去除整个蛋白质（PROTAC）。这些 可以用可光活化的或荧光分子或生物素标记，以实现靶识别， 验证、研究作用机制或表征相关的相互作用组。除了设计和 为了合成上述类型的小分子，PIP Core还将提供放大服务（mg至g）， 另外的实验，例如靶的体内验证和命中-引导优化研究， 构效关系数据。质谱法将用于表征这些影响， 通过蛋白质和翻译后或化学物质的定量分析， 修饰以验证可能导致耐药性的作用机制和补偿特征。 核心将由Natarajan博士和Woods博士领导，他们将为PIP核心带来补充性的专业知识。博士 Natarajan在开发探针、抑制剂和PROTAC方面拥有丰富的专业知识， 方法. Woods博士在使用质谱作为描绘蛋白质的平台方面拥有丰富的经验- 蛋白质相互作用、翻译后修饰和癌症对治疗反应的多变量生物标志物。 PIP核心服务将被CMTDD研究项目负责人（RPL）、CMTDD成员 和大学研究人员。