Pharmacological Inhibitors of Nedd4 ubiquitin ligase as anticancer therapeutics

Nedd4 泛素连接酶的药理学抑制剂作为抗癌疗法

• 批准号: 9302491
• 负责人: Alexander V Statsyuk
• 金额: $ 30.14万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302491
• 关键词: Address; Alkynes; Area; Autoimmune Diseases; Basic Science; Beta Cell; Binding; Biochemical; Biological Assay; Biological Process; Biology; Cell Line; Cell Proliferation; Cells; Crystallization; Cysteine; Development; Disease; Drug Targeting; Endocytosis; Enzyme Inhibitor Drugs; Enzymes; Essential Genes; Ewings sarcoma; FDA approved; Family; Foundations; Genetic Transcription; Genome; Germ-Line Mutation; Goals; Growth; Human; Human Biology; Insulin; Insulin Receptor; Insulin-Like Growth Factor I; Label; Ligase; Link; Malignant Neoplasms; Methods; Monoubiquitination; Mus; Neurodegenerative Disorders; Nuclear Import; PTEN gene; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphotransferases; Physiological; Polyubiquitin; Post-Translational Protein Processing; Protease Inhibitor; Proteins; Proteomics; Publishing; Research; Risk; Role; Signal Pathway; Signal Transduction; Somatic Mutation; Structure; Structure-Activity Relationship; Surface; Technology; Teratogens; Testing; Thalidomide; Therapeutic; Tumor Suppressor Proteins; Ubiquitination; X-Ray Crystallography; analog; anti-cancer therapeutic; base; cancer cell; cell growth; covalent bond; design; drug discovery; human disease; improved; inhibitor/antagonist; insight; kinase inhibitor; lenalidomide; novel; programs; protein protein interaction; public health relevance; small molecule; small molecule inhibitor; tool development; ubiquitin ligase; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Protein ubiquitination is a fundamental biological process that regulates all aspects of human biology. Covalent modification of proteins with polyubiquitin chains tags them for proteasomal degradation, while monoubiquitination regulates endocytosis, signal transduction, nuclear import, and gene transcription. To this end, ubiquitin ligase enzymes (~600 known) represent a vast and completely unexplored area of druggable genome. The complexity and diversity of ubiquitin ligases rivals that of three other large families of enzymes: kinases (~500), proteases (~600), and GPCRs (~800). There are 25 FDA approved kinase inhibitor drugs, ~30 FDA approved protease inhibitor drugs, and about 30% of all medications target GPCRs. In stark contrast, there are only 3 FDA approved drugs that target ubiquitin ligases: teratogenic compounds thalidomide, and its analogues lenalidomide and pomalidomide. Significantly, germline and somatic mutations of E3 ligase genes are linked to many human diseases such as cancers, autoimmune diseases, neurodegenerative diseases, and hypertensive disorders. Therefore E3 ligases have recently emerged as prominent targets for basic research and drug discovery. In this proposal, we focus our efforts on developing small molecule inhibitors of HECT E3 ligase Nedd4-1, which is an essential gene in mice and is a positive regulator of IGF-1 and insulin cell growth pathways, pathways that increase the risk and promote the growth of human cancers. Specific aims are as follows (1) To discover covalent inhibitors of Nedd4-1. We used an irreversible tethering technology, to identify two first-in-class covalent inhibitors of Nedd4-1 enzyme, and visualized their binding mode using X-ray crystallography. We propose to investigate biochemical mechanism of action of identified Nedd4-1 inhibitors, (2) conduct structure-activity relationship (SAR) studies of identified Nedd4 inhibitors, (3) to conduct cell based studies of Nedd4-1 inhibitors to show that they inhibit IGF-1/Insulin cell growth pathways in cells. In summary, the proposed research program outlines new concepts to discover covalent small molecule inhibitors of HECT E3 ubiquitin ligase Nedd4-1. The proposed research program will serve as a foundation to initiate novel research directions to discover and optimize small molecule probes targeting other HECT E3 ligases (28 known).

 描述(申请人提供)：蛋白质泛素化是一个基本的生物学过程，它调节人类生物学的各个方面。蛋白质与多泛素链的共价修饰标记了蛋白酶体的降解，而单泛素化则调节内吞作用、信号转导、核输入和基因转录。为此，泛素连接酶(已知约600个)代表了一个巨大的、完全未知的可用药基因组区域。泛素连接酶的复杂性和多样性可与其他三个大家族相媲美 酶类：激酶(~500)、蛋白水解酶(~600)和GPCRs(~800)。FDA批准的激酶抑制剂药物有25种，FDA批准的蛋白水解酶抑制剂药物有30种，约有30%的药物针对GPCRs。与之形成鲜明对比的是，FDA批准的针对泛素连接酶的药物只有3种：致畸化合物沙利度胺及其类似物来那度胺和泊马度胺。值得注意的是，E3连接酶基因的种系和体细胞突变与许多人类疾病有关，如癌症、自身免疫性疾病、神经退行性疾病和高血压疾病。因此，E3连接酶最近成为基础研究和药物发现的重要靶点。在这项建议中，我们集中精力开发Hect E3连接酶Nedd4-1的小分子抑制剂，这是小鼠的一个基本基因，是IGF-1和胰岛素细胞生长途径的正向调节因子，这些途径增加了人类癌症的风险并促进了人类癌症的生长。具体目标如下：(1)寻找Nedd4-1的共价抑制剂。我们使用了一种不可逆转的系链技术，识别出了两个一流的 Nedd4-1酶的共价抑制剂，并用X射线结晶学观察它们的结合模式。我们建议研究已鉴定的Ned4-1抑制剂的生化作用机制，(2)对已鉴定的Nedd4抑制剂进行构效关系(SAR)研究，(3)对Nedd4-1抑制剂进行基于细胞的研究，以表明它们抑制细胞内的IGF-1/Insulin细胞生长途径。总之，拟议的研究计划概述了发现Hect E3泛素连接酶Nedd4-1的共价小分子抑制剂的新概念。建议的研究计划将作为启动新的研究方向的基础，以发现和优化针对其他Hect E3连接酶(已知28个)的小分子探针。