Developing Ubiquitin Ligase Agonists as Cancer Therapeutics

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：鉴定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）靶向降解蛋白质并控制许多生物过程。UPS活性失调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，所有目前的治疗方法都涉及UPS抑制，这不能应用于使蛋白质降解失效的致癌突变。事实上，几个关键的肿瘤抑制因子是泛素化酶，它们在癌症中被突变失活。在许多癌症中，错义突变降低了泛素化酶与其蛋白质靶点之间的结合亲和力，这使得致癌底物积累并驱动致癌作用。这些突变也为新的治疗干预提供了独特的机会，我们建议开发小分子，恢复癌症中突变泛素化途径的功能。 Fbw 7 F-box蛋白是降解关键癌蛋白的SCF泛素连接酶的底物受体。Fbw 7是最常见的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，增加了相关的泛素连接酶与底物的结合，我们试图确定小分子，恢复结合亲和力突变Fbw 7蛋白在癌症中。我们将使用严格表征的高通量筛选平台来鉴定增加肿瘤衍生的Fbw 7蛋白与底物结合的激动剂。我们还开发了一系列独特的生物化学和生理学验证试验，以及用于化合物开发的结构和药物化学方法。如果成功，这项研究将建立一种新的药物治疗模式，靶向有缺陷的蛋白质降解途径。重要的是，我们工作的影响将超越Fbw 7，并促进类似的方法，靶向与Fbw 7相关的泛素化途径，这些途径也在癌症中突变。

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.