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

基本信息

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
项目类别：
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

项目摘要

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.

天然产物一直是抗击癌症的丰富疗法来源，包括广泛使用的太平洋红豆杉树皮产生的乳腺癌药物紫杉醇，通过靶向微管蛋白发挥作用，损害乳腺癌的致病性。虽然有无数的天然产品源自植物、微生物和其他已被证明具有抗癌活性的生物体，大多数的作用机制这些天然产物仍然知之甚少。其中一种天然产物是印楝内酯，一种三萜类化合物从印楝或印楝中提取，许多研究小组已证明其具有抗癌活性对抗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。我使用了一种创新的化学蛋白质组学平台，称为活性- 基于蛋白质分析 (ABPP)，它使用基于反应性的化学探针来绘制反应性、复杂蛋白质组中的功能性和可药物化热点，以绘制整个蛋白质组的可配体图谱抗癌天然产物印楝内酯针对乳腺癌细胞中的热点区域。我的初步使用 ABPP 的数据表明，印楝内酯选择性地靶向 231MFP 中 E3 泛素连接酶 RNF114 上的 C8 三阴性乳腺癌 (TNBC) 细胞，导致肿瘤抑制因子 p21 泛素化受损通过 RNF114 识别其蛋白质底物的能力受损。这反过来又导致 p21 水平升高，导致乳腺癌细胞致病性受损。在这个提案中，我将使用创新的化学生物学方法来确定印楝内酯的抗癌机制将 RNF114 描述为癌症治疗和靶向蛋白质降解应用的靶点。