New approaches to target protein intramolecular interactions

靶向蛋白质分子内相互作用的新方法

基本信息

批准号：
9285748
负责人：
JIANDONG CHEN
金额：
$ 18.71万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285748
关键词：
Adverse effects Apoptosis Promoter Binding Binding Proteins Biological Biological Assay Cell Death Deacetylase Development Disease Dissociation Enzyme Inhibitor Drugs Future In Vitro Investigation Lead Ligands Luciferases MDM2 gene Mediating Methods Modeling Modification Molecular Conformation Pathway interactions Peptides Phosphotransferases Protein p53 Proteins Regulation Retinoblastoma Protein Role SIRT1 gene Scaffolding Protein Screening procedure Signal Transduction Structure TP53 gene Therapeutic Therapeutic Intervention Tumor Suppressor Proteins Work biological adaptation to stress cancer therapy cell growth design drug development experimental study high throughput screening mimetics neoplastic cell new therapeutic target novel strategies peptidomimetics protein complex protein protein interaction small molecule success therapeutic target transcription factor

Adverse effects Apoptosis Promoter Binding Binding Proteins Biological Biological Assay Cell Death Deacetylase Development Disease Dissociation Enzyme Inhibitor Drugs Future In Vitro Investigation Lead Ligands Luciferases MDM2 gene Mediating Methods Modeling Modification Molecular Conformation Pathway interactions Peptides Phosphotransferases Protein p53 Proteins Regulation Retinoblastoma Protein Role SIRT1 gene Scaffolding Protein Screening procedure Signal Transduction Structure TP53 gene Therapeutic Therapeutic Intervention Tumor Suppressor Proteins Work biological adaptation to stress cancer therapy cell growth design drug development experimental study high throughput screening mimetics neoplastic cell new therapeutic target novel strategies peptidomimetics protein complex protein protein interaction small molecule success therapeutic target transcription factor

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项目摘要

Most current small molecule drugs are enzyme inhibitors or ligand-like molecules. They compete with natural substrates or ligands in deep binding pockets. Signal transduction often involves protein-protein interactions. Drug development has achieved some success in disrupting protein-protein interactions such as p53-MDM2 binding using small molecules and peptide mimetics. Our recent work suggests that intramolecular interactions mediate auto-activating or auto-inhibitory effects on MDM2 and MDMX, thus have important roles in regulating p53 activity and stress response. Our findings reveal potential new targets for the therapeutic modulation of p53. Intramolecular interaction has also been implicated in the regulation of numerous other proteins. However, stabilizing protein intramolecular interaction, the opposite of disrupting protein-protein binding, is largely unexplored as a therapeutic approach. We propose to use MDMX as a model to investigate the feasibility of stabilizing protein intramolecular interaction for p53 activation. Two specific aims are proposed: (1) Identify peptides that stabilize MDMX intramolecular interaction by in vitro compartmentalization screen. (2) Develop a high throughput screen for small molecules that stabilize MDMX intramolecular interaction. This work will provide proof of concept and lead compounds for the development of new drugs that target an important tumor suppressor pathway. Lessons from this study will also be applicable to the therapeutic targeting of other important disease-associated proteins.

当前大多数小分子药物是酶抑制剂或配体样药分子。他们与深层结合口袋中的天然底物或配体竞争。信号转导通常涉及蛋白质 - 蛋白质相互作用。药物开发有在破坏蛋白质 - 蛋白质相互作用（例如p53-MDM2）方面取得了成功使用小分子和肽模拟物结合。我们最近的工作表明分子内相互作用介导对MDM2的自动激活或自身抑制作用因此，MDMX在调节p53活性和应力反应中具有重要作用。我们的发现揭示了p53治疗调节的潜在新目标。分子内相互作用也与许多其他的调节有关蛋白质。但是，稳定蛋白质内相互作用，相反破坏蛋白质 - 蛋白质结合，在很大程度上没有探索作为治疗方法。我们建议使用MDMX作为模型来研究稳定蛋白的可行性 p53激活的分子内相互作用。提出了两个具体目标：（1）鉴定通过体外稳定MDMX分子内相互作用的肽隔室化屏幕。（2）为小的高吞吐量屏幕开发稳定MDMX分子内相互作用的分子。这项工作将提供概念证明和铅化合物，用于开发针对的新药重要的肿瘤抑制途径。这项研究的教训也适用于其他重要疾病相关蛋白的治疗靶向。