Probes, Inhibitors, and PROTACs (PIP) Core

探针、抑制剂和 PROTAC (PIP) 核心

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：探针、抑制剂和 PROTAC (PIP) 核心 PIP Core 的首要任务是使用复杂的化学和质谱分析促进分子靶标发现和开发的小分子的开发。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功能使用小分子相应的蛋白质。通常通过这些互补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可归因于依赖于多种功能的复杂生物学，即酶促和支架，与蛋白质靶标相关。通过改变核酸调节蛋白质水平消除所有目标蛋白质功能。然而，小分子调节剂可以调节以诱导任一域的特异性效应（可逆或不可逆）或通过精确的时间控制去除整个蛋白质（PROTAC）。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、研究作用机制或表征相关的相互作用组。除了设计和合成上述类型的小分子，PIP Core还将提供放大服务（mg到g）其他实验，例如目标的体内验证和命中到先导优化研究，以生成结构活动关系（SAR）数据。质谱分析将用于表征这些影响通过蛋白质定量分析和翻译后或化学分析蛋白质组上的化合物进行修改以验证可能有助于耐药性的作用机制和补偿特征。核心将由博士领导。 Natarajan 和 Woods 将为 PIP Core 带来互补的专业知识。博士。 Natarajan 在利用尖端化学技术开发探针、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 成员广泛使用和广大大学研究人员。