Discovery of Small Molecule Inhibitors of the DCN1-UBC12 Interaction

DCN1-UBC12 相互作用的小分子抑制剂的发现

• 批准号: 8830740
• 负责人: Jared Thomas Hammill
• 金额: $ 5.42万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8830740
• 关键词: 26S proteasome; Address; Attention; Bacterial Infections; Binding; Biochemical; Biological; Biological Assay; Biological Availability; Cell model; Cells; Chemicals; Crystallography; Cullin Proteins; Development; Disease; Ensure; Enzymes; Evaluation; FDA approved; Family; Foundations; Goals; Government; Head; Homeostasis; Human; In Vitro; Inhibitory Concentration 50; Intervention; Lead; Life; Ligase; Malignant Neoplasms; Mediating; Modeling; Molecular; Neurodegenerative Disorders; Pathway interactions; Permeability; Persons; Pharmaceutical Preparations; Play; Process; Proteins; Regulation; Research; Role; Series; Solubility; Solutions; Squamous Cell Lung Carcinoma; System; Therapeutic; Ubiquitin; Ubiquitin-Activating Enzymes; Ubiquitin-Conjugating Enzymes; Ubiquitination; Validation; Viral; Virus Diseases; base; biophysical analysis; cancer therapy; clinically relevant; high throughput screening; improved; in vivo; in vivo Model; inhibitor/antagonist; multicatalytic endopeptidase complex; novel therapeutics; protein degradation; protein protein interaction; public health relevance; screening; small molecule; tool; tumor growth; ubiquitin ligase; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): The ubiquitin-proteasome system (UPS), which controls the degradation of proteins inside the cell, plays an integral role in maintaining cellula protein homeostasis. Dysregulation of the UPS is associated with a growing number of diseases including cancers, neurodegenerative disorders, and viral and bacterial infections. As a result, regulators of the UPS have received considerable attention for developing new human therapeutics. The current FDA approved therapeutics, which target the UPS, are efficacious but also fairly toxic - probably because they completely shut down the activity of the UPS. This proposal seeks to address this problem by developing small molecule inhibitors of DCN1 that regulate the UPS without completely blocking its activity. DCN1 is a recently identified protein whose dysregulation is associated with a number of human cancers. DCN1 activity is controlled by its interaction with UBC12. Therefore, the goal of this proposal is to develop potent and selective small molecule inhibitors that disrupt the DCN1-UBC12 protein-protein interaction and use them to elucidate the biological effects of DCN1 mediated UPS regulation. Aim 1 addresses the optimization of DCN1-UBC12 interaction inhibitors, identified by a high-throughput screening campaign, based on biochemical potency and models for cellular and organismal bioavailability. Aim 2 addresses whether or not chemical disruption of the DCN1-UBC12 interaction functionally and selectively inhibits neddylation, cullin-RING E3 ligase activity, UPS activity, and effectively suppresses tumor growth in clinically relevant in vivo models. If the DCN1-UBC12 interaction is validated as a target for regulation of the UPS, this new mechanism of action will provide a useful tool for elucidating the molecular mechanisms of DCN1 mediated CRL activity and regulation of the UPS. These studies will increase our understanding of a key life process and potentially lay the foundation for significant advances in the development of highly selective therapeutics.

 描述（由申请人提供）：泛素蛋白酶体系统（UPS）控制细胞内蛋白质的降解，在维持细胞蛋白质稳态中发挥着不可或缺的作用。 UPS 失调与越来越多的疾病有关，包括癌症、神经退行性疾病以及病毒和细菌感染。因此，UPS 监管机构在开发新的人类疗法方面受到了相当大的关注。目前 FDA 批准的针对 UPS 的疗法虽然有效，但毒性也相当大 - 可能是因为它们完全关闭了 UPS 的活动。该提案旨在通过开发 DCN1 的小分子抑制剂来解决这个问题，这些抑制剂可以调节 UPS 而不会完全阻止其活动。 DCN1 是最近发现的一种蛋白质，其失调与多种人类癌症有关。 DCN1 活性由其与 UBC12 的相互作用控制。因此，本提案的目标是开发有效的、选择性的小分子抑制剂，破坏 DCN1-UBC12 蛋白质-蛋白质相互作用，并利用它们来阐明 DCN1 介导的 UPS 调节的生物学效应。目标 1 解决 DCN1-UBC12 相互作用抑制剂的优化问题，该抑制剂是通过基于生化效力以及细胞和有机体生物利用度模型的高通量筛选活动确定的。目标 2 解决 DCN1-UBC12 相互作用的化学破坏是否功能性和选择性地抑制 neddylation、cullin-RING E3 连接酶活性、UPS 活性，并有效 在临床相关的体内模型中抑制肿瘤生长。如果 DCN1-UBC12 相互作用被验证为 UPS 调节的目标，那么这种新的作用机制将为阐明 DCN1 介导的 CRL 活性和 UPS 调节的分子机制提供有用的工具。这些研究将增加我们对关键生命过程的理解，并有可能为高度选择性疗法的开发取得重大进展奠定基础。