Discovery of UHRF1 inhibitors in the treatment of hepatocellular carcinoma

UHRF1抑制剂治疗肝细胞癌的发现

• 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
• 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

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.

项目概要（试点项目1） 这项合作试点提案的首要目标是开发一种新的治疗方法， 肝细胞癌（HCC）-一种以较高的比率影响美国代表性不足的人群的癌症。 HCC的特征之一是DNA低甲基化的整体水平的表现，这有助于 肿瘤进展和转移。虽然表观遗传治疗方法正在兴起，但 目前还没有药物能在机制上减少DNA低甲基化。为了治疗 我们将开发减少DNA的化合物， 通过新的治疗靶点进行低甲基化。具有植物和同源结构域的泛素样蛋白（PHD）， 真正有趣的新基因（RING）指结构域1（UHRF 1）是DNA甲基化的主要调节因子。 UHRF 1的过表达驱动HCC和肿瘤进展中的DNA低甲基化。UHRF 1是E3连接酶 通过泛素化影响从头DNA甲基转移酶DNMT 3A的负调控， 降解DNMT 3A的缺失反过来导致癌症中的整体低甲基化。作为一种手段， 为了减少HCC中的整体低甲基化，该试点项目的重点是开发小- 抑制UHRF 1-DNMT 3A蛋白-蛋白相互作用（PPI）的分子或类肽。的化合物 抑制这种相互作用将拯救HCC细胞中DNMT 3A水平，导致基因组DNA水平降低， 低甲基化和减轻HCC增殖。为了鉴定作为UHRF 1- DNMT 3A抑制剂，我们在具体目标1中提出以并行方式部署两个发现平台：DNA- 编码化学技术（DEC-Tec）和珠上类肽筛选。每个平台都提供 一个经济的进入一个大的化学空间，可能需要确定化合物能够 破坏UHRF 1-DNMT 3A相互作用。在具体目标2的支持下，我们将评估生物 通过对癌细胞系进行一系列生物学测定来研究UHRF 1-DNMT 3A抑制剂的作用 从非裔美国人和西班牙裔/拉丁裔患者获得的HCC肿瘤产生。这些非常有用的 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， 易患HCC。我们将确定低甲基化还原化合物对细胞DNA的影响 甲基化水平、基因表达和癌细胞增殖和凋亡。药物化学将是 以提高化合物效力和生物功效，从而产生大约六种最终化合物 我们将对此进行初步的药理学研究。该项目的顺利完成将 为HCC的治疗提供了一种新的治疗机制， 严重影响了乌拉圭人民。