Inhibitor mediated protein degradation

抑制剂介导的蛋白质降解

基本信息

批准号：
8270782
负责人：
Lizbeth K. Hedstrom
金额：
$ 30.31万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270782
关键词：
Affinity Affinity Chromatography Animal Model Arginine Basic Science Biocompatible Biological Biological Assay Biological Process Carbamates Cells Chimeric Proteins DHFR gene DNA Repair Enzymes Dasatinib Dihydrofolate Reductase Dissociation Elements Escherichia coli Ethacrynic Acid Glutathione S-Transferase Hereditary Disease Investigation Ligands Link Mediating Methods NMR Spectroscopy Organism Pathway interactions Pharmacologic Substance Phosphotransferases Post-Translational Regulation Proteins S-nitro-N-acetylpenicillamine Structure-Activity Relationship System Technology Translational Research Trimethoprim Work cancer therapy chemotherapy drug discovery effective therapy inhibitor/antagonist multicatalytic endopeptidase complex novel novel strategies protein degradation protein expression protein function research study small molecule tool

项目摘要

DESCRIPTION (provided by applicant): A formidable toolkit exists for manipulating protein expression at the transcriptional level, but the methods for the post-translational modulation of proteins are few and of limited utility. A small molecule that induces degradation of endogenous proteins would clearly be a tremendously useful tool for probing protein function and an exciting approach for chemotherapy. The challenge is to develop technology that is biocompatible and widely applicable. We have serendipitously discovered a moiety that when combined with a recognition element, induces degradation of the target protein. We propose to characterize this phenomenon and develop these novel tools for protein knockdown that will be invaluable in a broad array of biological and pharmaceutical applications. PUBLIC HEALTH RELEVANCE: The ability to manipulate protein levels is invaluable in investigations of biological function, so if successful, this proposal will have an enormous impact in the basic science arena. The potential impact in drug discovery is also substantial: the ability to induce the degradation of pathogenic proteins is expected to be much more effective treatment than current inhibition strategies. The promise of such an approach is readily apparent in the treatment of cancer and hereditary diseases.

描述（由申请人提供）：存在用于在转录水平操纵蛋白质表达的强大工具包，但用于蛋白质翻译后调节的方法很少且实用性有限。诱导内源性蛋白质降解的小分子显然将是探测蛋白质功能的非常有用的工具，也是令人兴奋的化疗方法。挑战在于开发生物相容且广泛适用的技术。我们偶然发现了一个部分，当与识别元件结合时，会诱导目标蛋白的降解。我们建议描述这种现象，并开发这些用于蛋白质敲低的新工具，这在广泛的生物和制药应用中将具有无价的价值。公共卫生相关性：操纵蛋白质水平的能力在生物功能研究中非常宝贵，因此如果成功，该提案将产生巨大影响在基础科学领域。对药物发现的潜在影响也是巨大的：诱导致病蛋白降解预计是比目前的抑制策略更有效的治疗方法。这种方法的前景在癌症和遗传性疾病的治疗中是显而易见的。