Discovery of UHRF1 inhibitors in the treatment of hepatocellular carcinoma

UHRF1抑制剂治疗肝细胞癌的发现

基本信息

批准号：
9789847
负责人：
Damian Winston Young
金额：
$ 9.73万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9789847
关键词：
Address Affect African American Antineoplastic Agents Apoptosis BAY 54-9085 Binding Biological Biological Assay Cancer cell line Catalytic Domain Caucasians Cell Proliferation Cells Chemicals Chemistry Chromosomal Instability DNA DNA Methylation DNA Modification Methylases Development Diagnosis Disease Education Epigenetic Process Evaluation FDA approved Fingers Gene Expression Genes Genetic Genomics Goals Hepatocyte Hispanics Human Incidence Individual Latino Ligands Luciferases Malignant Epithelial Cell Malignant Neoplasms Medical Methods Methylation Neoplasm Metastasis Oncogene Activation Operative Surgical Procedures Outcome PHD Finger Pathway interactions Patients Peptoids Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacology Study Pilot Projects Plants Population Primary carcinoma of the liver cells Property Proteins Regulation Reporter Retrotransposon Ring Finger Domain Sampling Technology Testing Therapeutic Treatment Efficacy Tumor Suppressor Genes Ubiquitin Ubiquitination Underrepresented Populations United States Western Blotting base cancer cell cytotoxicity daughter cell derepression drug discovery effective therapy genome wide methylation hepatocellular carcinoma cell line high risk high throughput screening homeodomain improved inhibitor/antagonist innovation kinase inhibitor liver transplantation methylome negative affect neoplastic cell new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics outcome forecast overexpression prognostic programs protein protein interaction recruit screening small molecule success tumor tumor progression ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY (PILOT PROJECT 1) The overarching goal of this collaborative pilot proposal is the development of a novel approach to treat hepatocellular carcinoma (HCC)—a cancer affecting underrepresented populations in the US at a higher rate. One of the signatures of HCC is the manifestation of global levels of DNA hypomethylation which contributes to tumor progression and metastasis. Although epigenetic therapeutic approaches are on the rise, there are currently no drugs that mechanistically function to reduce DNA hypomethylation. Toward the goal of treating UR populations that are significantly impacted by HCC, we will develop compounds that reduce DNA hypomethylation through a novel therapeutic target. Ubiquitin-like with plant and homeodomain (PHD) and really interesting new gene (RING) finger domains 1 (UHRF1) is a master regulator of the DNA methylome. Overexpression of UHRF1 drives DNA hypomethylation in HCC and tumor progression. UHRF1 is an E3 ligase that affects the negative regulation of the de novo DNA methyltransferase DNMT3A through ubiquitination and degradation. Loss of DNMT3A, in turn, leads to global hypomethylation in cancers. Therefore, as a means toward reducing global hypomethylation in HCC, the focus of this pilot project is the development small- molecules or peptoids that inhibit the UHRF1-DNMT3A protein-protein interaction (PPI). Compounds that inhibit this interaction will rescue DNMT3A levels in HCC cells leading to decreases in genomic hypomethylation and the mitigation of HCC proliferation. To identify compounds that function as UHRF1- DNMT3A inhibitors, we propose in Specific Aim 1 to deploy two discovery platforms in a parallel fashion: DNA- Encoded Chemistry Technology (DEC-Tec) and on-bead peptoid screening. Each of these platforms provides an economical access to a large chemical space that will likely be needed to identify compounds capable of disrupting the UHRF1-DNMT3A interaction. Under the aegis of Specific Aim 2, we will evaluate the biological effects of the UHRF1-DNMT3A inhibitors by executing a suite of biological assays on cancer cell lines generated from HCC tumors obtained from African American and Hispanic/Latino patients. These highly useful cancer cell lines will allow us to develop our compounds within the genetic backgrounds of populations most susceptible to HCC. We will determine the effects of hypomethylation reducing compounds on cellular DNA methylation levels, gene expression, and cancer cell proliferation and apoptosis. Medicinal chemistry will be performed to improve compound potency and biological efficacy leading to approximately six final compounds for which we will conduct preliminary pharmacological studies. The successful completion of this project will afford a novel therapeutic mechanism for the treatment of HCC and have particularly salutary relevance within greatly affected UR populations.

项目摘要（试点项目 1）该合作试点提案的总体目标是开发一种新方法来治疗肝细胞癌 (HCC)——一种以较高比率影响美国代表性不足人群的癌症。 HCC 的特征之一是整体 DNA 低甲基化水平的表现，这有助于尽管表观遗传学治疗方法正在兴起，但仍存在一些问题。目前还没有药物能够从机制上起到减少 DNA 低甲基化的作用，从而达到治疗的目标。受 HCC 影响显着的 UR 人群，我们将开发减少 DNA 的化合物通过植物和同源结构域（PHD）的新型泛素样治疗靶点进行低甲基化真正有趣的新基因 (RING) 指状结构域 1 (UHRF1) 是 DNA 甲基化组的主要调节因子。 UHRF1 的过度表达会导致 HCC 中的 DNA 低甲基化，并且 UHRF1 是一种 E3 连接酶。通过泛素化影响从头 DNA 甲基转移酶 DNMT3A 的负调控 DNMT3A 的缺失反过来会导致癌症中的整体低甲基化。为了减少 HCC 的全球低甲基化，该试点项目的重点是开发小抑制 UHRF1-DNMT3A 蛋白质-蛋白质相互作用 (PPI) 的分子或类肽化合物。抑制这种相互作用将挽救 HCC 细胞中的 DNMT3A 水平，从而导致基因组鉴定具有 UHRF1- 功能的化合物。 DNMT3A 抑制剂，我们在具体目标 1 中建议以并行方式部署两个发现平台：DNA- 这些平台均提供编码化学技术 (DEC-Tec) 和珠上肽筛选。经济上可以进入大型化学空间，可能需要识别有能力的化合物在特定目标 2 的支持下，我们将评估其生物学特性。通过对癌细胞系进行一系列生物测定来了解 UHRF1-DNMT3A 抑制剂的作用由非裔美国人和西班牙裔/拉丁裔患者的 HCC 肿瘤产生，这些非常有用。癌细胞系将使我们能够在大多数人群的遗传背景下开发我们的化合物我们将确定低甲基化对细胞 DNA 的影响。甲基化水平、基因表达以及癌细胞增殖和凋亡将受到影响。进行以提高化合物效力和生物功效，产生大约六种最终化合物为此我们将进行初步的药理学研究，该项目的成功完成将。为 HCC 的治疗提供了一种新的治疗机制，并且在以下领域具有特别有益的意义：极大地影响了UR人群。