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

基本信息

批准号：
9100801
负责人：
Alexander V Statsyuk
金额：
$ 2.41万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9100801
关键词：
Address Alkynes Area Autoimmune Diseases Basic Science Beta Cell Binding Biochemical Biological Assay Biological Process Biology Cell Line Cell Proliferation Cells Cysteine Development Disease Drug Targeting Endocytosis Enzyme Inhibitor Drugs Enzyme Inhibitors 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 Lead 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 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

项目摘要

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（由申请人提供）：蛋白质泛素化是调节人类生物学各个方面的基本生物过程，用多泛素链标记蛋白质进行蛋白酶体降解，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 种）代表了可药物基因组的广阔且完全未经探索的领域的复杂性和。泛素连接酶的多样性可与其他三个大家族相媲美酶：激酶 (~500)、蛋白酶 (~600) 和 GPCR (~800) 有 25 种 FDA 批准的激酶抑制剂药物，约 30 种 FDA 批准的蛋白酶抑制剂药物，约 30% 的药物以 GPCR 为目标。形成鲜明对比的是，只有 3 种 FDA 批准的靶向泛素连接酶的药物：致畸化合物沙利度胺及其类似物来那度胺和值得注意的是，E3 连接酶基因的种系和体细胞突变与许多人类疾病有关，例如癌症、自身免疫性疾病、神经退行性疾病和高血压疾病，因此 E3 连接酶最近已成为基础研究和药物发现的重要靶点。根据提案，我们重点开发 HECT E3 连接酶 Nedd4-1 的小分子抑制剂，Nedd4-1 是小鼠体内的必需基因，是 IGF-1 和 IGF-1 的正调节因子胰岛素细胞生长途径，增加人类癌症风险和促进生长的途径如下： (1) 发现 Nedd4-1 的共价抑制剂，我们使用不可逆束缚技术，鉴定了两种一流的抑制剂。 Nedd4-1 酶的共价抑制剂，并使用 X 射线晶体学可视化其结合模式，我们建议研究已确定的 Nedd4-1 抑制剂的生化机制，（2）对已确定的 Nedd4 抑制剂进行构效关系（SAR）研究。，（3）对 Nedd4-1 抑制剂进行细胞研究，以表明它们抑制细胞中的 IGF-1/胰岛素细胞生长途径。总之，拟议的研究计划概述了发现共价小分子的新概念。 HECT E3 泛素连接酶 Nedd4-1 的分子抑制剂拟议的研究计划将作为启动新研究方向的基础，以发现和优化针对其他 HECT E3 连接酶（28 种已知）的小分子探针。