m6A-RNA demethylase ALKBH5 inhibitors for the treatment of glioblastoma

m6A-RNA 去甲基化酶 ALKBH5 抑制剂用于治疗胶质母细胞瘤

• 批准号: 10043670
• 负责人: TARIQ M RANA
• 金额: $ 43.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043670
• 关键词: 3-Dimensional; Adult; Alkylation; Biological Assay; Biological Models; Brain Neoplasms; Cells; Characteristics; Chemicals; Chemotherapy and/or radiation; Child; Collaborations; Deposition; Drug Design; Drug Kinetics; Enzyme Kinetics; Enzymes; Gene Expression; Glioblastoma; Goals; Homologous Gene; Homologous Protein; In Vitro; Infiltration; Life Expectancy; Longevity; Malignant Neoplasms; Messenger RNA; Modeling; Modification; Mus; Nucleotides; Organoids; Outcome; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Population; Post-Transcriptional Regulation; Property; RNA; RNA metabolism; Radiation therapy; Reader; Recombinants; Recurrence; Regulation; Resistance; Role; Site; Survival Rate; Testing; Therapeutic Agents; Undifferentiated; Work; antiproliferative agents; chemical property; chemotherapeutic agent; design; drug development; drug discovery; epitranscriptomics; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; knock-down; novel; outcome forecast; repaired; small molecule inhibitor; stem; therapeutic target; tumor; tumor progression; tumorigenesis

Epitranscriptomics is an emerging field that seeks to identify and understand chemical modifications in RNA; the enzymes that deposit, remove, and interpret the modifications (writers, erasers, and readers, respectively); and their effects on gene expression via regulation of RNA metabolism, function, and localization. Glioblastoma multiforme (GBM) is the deadliest brain tumor identified in both adults and children, with an average life expectancy of 15 months. GBM is characterized by high rates of both tumor infiltration and recurrence and is often resistant to treatment with radiation and chemotherapy. These characteristics have been attributed to the presence of undifferentiated glioblastoma tumor-initiating cells or glioblastoma stem-like tumor initiating cells (GSCs). Recent studies have shown that cells depleted in N6- methyladenosine (m6A) RNA modifications are resistant to differentiation, and it is suspected that misregulation of the reversible m6A pathway may play a role in generating tumor-initiating cells and promoting tumorigenesis. ALKBH5 expression is elevated in primary and established GBM cells enriched with GSCs, and high expression is correlated with poor prognosis in GBM patients. The objective of this proposal is to identify and develop novel inhibitors of the RNA demethylase alkylation repair homolog protein 5 (ALKBH5) as potential chemotherapeutics for glioblastoma multiforme. Our project has three aims. Aim 1: to optimize leads as potent and selective inhibitors of ALKBH5 with rational drug design. Aim 2: to establish the enzymatic and cellular mechanism of action of ALKBH5 inhibitors. Aim 3: to establish ALKBH5 inhibitors as effective antiproliferative agents in GSCs. The expected outcome of this work is a chemically diverse set of the first ALKBH5 inhibitors. This project will provide a clear positive impact by providing important groundwork for developing ALKBH5-targeted treatments of GBM.

同意组合是一个新兴领域，旨在识别和理解化学 RNA的修饰；沉积，去除和解释修饰的酶 （作家，橡皮图和读者分别）；以及它们通过调节对基因表达的影响 RNA代谢，功能和本地化的作用。胶质母细胞瘤多形（GBM）是最致命的 脑肿瘤在成人和儿童中都鉴定出来，平均预期寿命为15个月。 GBM的特征是肿瘤浸润和复发率高，并且通常是 对放射和化学疗法的治疗有抵抗力。这些特征已经 归因于存在未分化的胶质母细胞瘤肿瘤发射细胞或胶质母细胞瘤 茎状肿瘤引发细胞（GSC）。最近的研究表明，在N6-中耗尽的细胞 甲基腺苷（M6A）RNA修饰具有抗分化性，可疑 可逆的M6A途径的不调节可能在产生肿瘤发作中发挥作用 细胞并促进肿瘤发生。 ALKBH5表达在原发性和建立中升高 富含GSC的GBM细胞，高表达与GBM的预后不良相关 患者。该建议的目的是识别和开发RNA的新型抑制剂 去甲基酶烷基化修复同源蛋白5（ALKBH5）作为潜在的化学治疗药 胶质母细胞瘤多形。我们的项目有三个目标。目的1：将铅优化为有效，并且 具有合理药物设计的ALKBH5的选择性抑制剂。目标2：建立酶促和 ALKBH5抑制剂的作用机理。目标3：将ALKBH5抑制剂建立为 GSC中有效的抗增生剂。这项工作的预期结果是化学上的 第一个ALKBH5抑制剂的多样化集。该项目将带来明显的积极影响 为开发GBM的ALKBH5靶向疗法提供了重要的基础。