Developing Ubiquitin Ligase Agonists as Cancer Therapeutics

开发泛素连接酶激动剂作为癌症治疗药物

基本信息

批准号：
8562191
负责人：
Bruce E Clurman
金额：
$ 46.25万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8562191
关键词：
Affect Affinity Agonist Animal Model Arginine Auxins Binding Biochemical Biological Assay Biological Process Cancer Biology Cell division Cells Clinical Trials Cyclin E Degradation Pathway Development Disabled Persons Disease Enzymes F Box Domain F-Box Proteins Funding Genes Goals Hot Spot Human Length Libraries Malignant Neoplasms Metabolism Missense Mutation Mutate Mutation Normal Cell Oncogene Proteins Oncogenic Pathogenesis Pathway interactions Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Physiological Plant Growth Regulators Proteasome Inhibition Proteins Proto-Oncogenes Research Role Structural Chemistry Structure Substrate Interaction Suppressor Mutations System Therapeutic Tumor Suppressor Proteins Tumor-Derived Ubiquitin Universities Validation Washington Work base cancer cell cancer therapy carcinogenesis clinical care clinical practice drug discovery follow-up functional restoration high throughput screening inhibitor/antagonist loss of function mutation multicatalytic endopeptidase complex mutant notch protein novel therapeutic intervention novel therapeutics null mutation prevent protein degradation public health relevance receptor reconstitution screening small molecule structural biology therapeutic target tumor tumorigenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a new concept in cancer therapy: to identify small molecules that restore the function of ubiquitin ligases that are mutated in cancers. The ubiquitin-proteasome system (UPS) targets proteins for degradation and controls many biological processes. Misregulated UPS activity has profound physiologic consequences and contributes to the pathogenesis of many diseases, including cancer. Tumors often contain mutations in ubiquitylation enzymes that either enhance or disable UPS function, depending on the affected gene. The UPS is thus an important therapeutic target in cancer and UPS inhibitors have already impacted clinical care. However, all current therapeutic approaches involve UPS inhibition, which cannot be applied to oncogenic mutations that disable protein degradation. Indeed, several key tumor suppressors are ubiquitylation enzymes that are inactivated by mutations in cancer. In many cancers, missense mutations reduce the binding affinity between ubiquitylation enzymes and their protein targets, and this allows oncogenic substrates to accumulate and drive carcinogenesis. These mutations also provide a unique opportunity for a novel therapeutic intervention, and we propose to develop small molecules that restore function to mutant ubiquitylation pathways in cancers. The Fbw7 F-box protein is the substrate receptor of an SCF ubiquitin ligase that degrades critical oncoproteins. Fbw7 is one of the most commonly mutated human tumor suppressors, and these mutations often involve missense mutations that prevent substrate binding. Based on our finding that a plant hormone, auxin, functions as a natural small-molecule agonist that increases the binding of a related ubiquitin ligase to substrates, we seek to identify small molecules that restore binding affinity to mutant Fbw7 proteins in cancers. We will use a rigorously characterized high-throughput screening platform to identify agonists that increase the binding of tumor-derived Fbw7 proteins to substrates. We have also developed a unique array of biochemical and physiologic validation assays, as well as structural and medicinal chemistry approaches for compound development. If successful, this research will establish a new paradigm of drug therapy that targets defective protein degradation pathways. Importantly, our work's impact will extend beyond Fbw7, and facilitate similar approaches that target ubiquitylation pathways related to Fbw7 that are also mutated in cancers.

描述（由申请人提供）：该提案的目标是开发癌症治疗的新概念：识别能够恢复癌症中突变的泛素连接酶功能的小分子。泛素蛋白酶体系统（UPS）以蛋白质为目标进行降解并控制许多生物过程。 UPS 活动失调会产生深远的生理后果，并导致包括癌症在内的许多疾病的发病机制。肿瘤通常含有泛素化酶突变，这些突变会增强或禁用 UPS 功能，具体取决于受影响的基因。因此，UPS 是癌症的重要治疗靶点，UPS 抑制剂已经影响了临床护理。然而，目前所有的治疗方法都涉及 UPS 抑制，这不能应用于阻止蛋白质降解的致癌突变。事实上，一些关键的肿瘤抑制因子是泛素化酶，它们会因癌症突变而失活。在许多癌症中，错义突变降低了泛素化酶与其蛋白质靶标之间的结合亲和力，这使得致癌底物积累并驱动致癌作用。这些突变也为新型治疗干预提供了独特的机会，我们建议开发小分子来恢复癌症中突变泛素化途径的功能。 Fbw7 F-box 蛋白是 SCF 泛素连接酶的底物受体，可降解关键的癌蛋白。 Fbw7 是最常见突变的人类肿瘤抑制因子之一，这些突变通常涉及阻止底物结合的错义突变。基于我们发现植物激素生长素作为天然小分子激动剂，增加相关泛素连接酶与底物的结合，我们寻求鉴定能够恢复与癌症中突变 Fbw7 蛋白的结合亲和力的小分子。我们将使用经过严格表征的高通量筛选平台来鉴定能够增加肿瘤来源的 Fbw7 蛋白与底物结合的激动剂。我们还开发了一系列独特的生化和生理验证分析，以及用于化合物开发的结构和药物化学方法。如果成功，这项研究将建立一种针对有缺陷的蛋白质降解途径的药物治疗新范例。重要的是，我们工作的影响将超越 Fbw7，并促进针对与 Fbw7 相关的泛素化途径的类似方法，这些途径也在癌症中发生突变。