Targeting RNF114 for Cancer Therapy and Targeted Protein Degradation

靶向 RNF114 进行癌症治疗和靶向蛋白质降解

• 批准号: 9889798
• 负责人: Jessica Nichole Spradlin
• 金额: $ 2.81万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2020-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889798
• 关键词: Antineoplastic Agents; Azadirachta indica; Binding; Biology; Breast Cancer Cell; Chemicals; Colon Carcinoma; Complex; Cysteine; Data; Impairment; In Situ; In Vitro; Libraries; Ligands; Malignant Neoplasms; Maps; Microbe; Modality; Modification; Mus; Natural Products; Organism; Paclitaxel; Pathogenicity; Plants; Primary carcinoma of the liver cells; Property; Protac; Proteins; Proteome; Renal Cell Carcinoma; Reporting; Role; Source; Taxus; Technology; Testing; Therapeutic; Tubulin; Tumor Suppressor Proteins; Ubiquitination; activity-based protein profiling; anti-cancer; anticancer activity; base; cancer cell; cancer therapy; cancer type; cell type; chemoproteomics; combat; drug discovery; in vivo; inhibitor/antagonist; innovation; interest; malignant breast neoplasm; novel; professor; protein degradation; receptor; recruit; scaffold; screening; targeted cancer therapy; triple-negative invasive breast carcinoma; ubiquitin-protein ligase

Natural products have been a prolific source of therapeutics for combatting cancers, including the widely-used breast cancer drug taxol produced by the bark of the Pacific yew that acts through targeting tubulin to impair breast cancer pathogenicity. While there are countless natural products derived from plants, microbes, and other living organisms that have been shown to exert anti-cancer activity, the mechanism of action of most of these natural products remain poorly understood. One such natural product is nimbolide, a triterpenoid obtained from Azadirachta indica or neem, that has been shown by many groups to exert anti-cancer activity against multiple different types of cancers, including breast cancers, hepatocellular carcinomas, colon cancers, and renal cell carcinomas. While this natural product possesses compelling anti-cancer properties, the direct targets remain poorly understood. I have used an innovative chemoproteomic platform termed activity- based protein profiling (ABPP), which uses reactivity-based chemical probes to map reactive, functional, and druggable hotspots in complex proteomes, to map the proteome-wide ligandable hotspots targeted by the anti-cancer natural product nimbolide in breast cancer cells. My preliminary data using ABPP indicate that nimbolide selectively targets C8 on the E3 ubiquitin ligase RNF114 in 231MFP triple-negative breast cancer (TNBC) cells, leading to impaired ubiquitination of the tumor suppressor p21 through an impairment in the ability of RNF114 to recognize its protein substrates. This in-turn leads to an elevation in p21 levels, leading to impaired breast cancer cell pathogenicity. In this proposal, I will use innovative chemical biology approaches to determine the anti-cancer mechanisms of nimbolide and characterize RNF114 as a target for cancer therapy and for targeted protein degradation applications.

天然产品一直是对抗癌症的多产疗法来源，包括广泛使用的癌症 太平洋紫杉的树皮生产的乳腺癌药物紫杉醇通过靶向微管蛋白而造成损害 乳腺癌的致病性。虽然有无数的天然产品来自植物，微生物和 其他已证明具有抗癌活性的生物体，大多数的作用机理 这些天然产物的理解仍然很差。一种这种天然产品是nimbolide，一种三萜 从Azadirachta或Neem获得的，许多组已显示出抗癌活性 针对多种不同类型的癌症，包括乳腺癌，肝细胞癌，结肠癌， 和肾细胞癌。虽然这种天然产品具有引人注目的抗癌特性，但直接 目标仍然知之甚少。我使用了一个创新的化学蛋白质组平台称为活性 - 基于基于反应性的化学探针绘制反应性的基于蛋白质分析（ABPP）， 复杂蛋白质组中的功能和可毒的热点，以绘制全蛋白质组的可韧带 由抗癌天然产物Nimbolide在乳腺癌细胞中靶向的热点。我的初步 使用ABPP的数据表明，Nimbolide在231MFP中选择性地靶向E3泛素连接酶RNF114上的C8 三阴性乳腺癌（TNBC）细胞，导致肿瘤抑制p21的泛素化受损 通过损害RNF114识别其蛋白质底物的能力。这个弯曲导致 p21水平的升高导致乳腺癌细胞致病性受损。在此提案中，我将使用 创新的化学生物学方法来确定Nimbolide和Nimbolide的抗癌机制 将RNF114表征为癌症治疗和靶向蛋白质降解应用的靶标。