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

• 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
• 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

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）：本提案的目标是在癌症治疗中发展一个新概念：识别恢复泛素连接酶功能的小分子，这些泛素连接酶在癌症中突变。泛素-蛋白酶体系统（UPS）针对蛋白质的降解和控制许多生物过程。失调的UPS活性具有深远的生理后果，并有助于许多疾病的发病机制，包括癌症。肿瘤通常含有泛素化酶的突变，根据受影响的基因，这些突变可以增强或禁用UPS功能。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抑制UPS，这不能应用于使蛋白质降解失效的致癌突变。事实上，一些关键的肿瘤抑制因子是泛素化酶，它们在癌症中因突变而失活。在许多癌症中，错义突变降低了泛素化酶与其蛋白靶点之间的结合亲和力，这使得致癌底物积累并驱动癌变。这些突变也为新的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的泛素化途径的功能。Fbw7 F-box蛋白是降解关键癌蛋白的SCF泛素连接酶的底物受体。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。基于我们的发现，植物激素生长素作为一种天然的小分子激动剂，可以增加相关的泛素连接酶与底物的结合，我们寻求识别在癌症中恢复与突变Fbw7蛋白结合亲和力的小分子。我们将使用严格表征的高通量筛选平台来鉴定能够增加肿瘤源性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试验，以及用于化合物开发的结构和药物化学方法。如果成功，这项研究将建立一个针对缺陷蛋白质降解途径的药物治疗的新范例。重要的是，我们工作的影响将超越Fbw7，并促进类似的方法，靶向与Fbw7相关的泛素化途径，这些泛素化途径也在癌症中发生突变。