m6A-RNA demethylase ALKBH5 inhibitors for the treatment of glioblastoma

表位转录组学是一个新兴的领域，旨在识别和理解化学 RNA中的修饰;存款、去除和解释修饰的酶 （分别为书写者、擦除者和阅读者）;以及它们通过调控对基因表达的影响 RNA的代谢、功能和定位。多形性胶质母细胞瘤（GBM）是最致命的 在成人和儿童中发现的脑肿瘤，平均预期寿命为15个月。 GBM的特征在于肿瘤浸润和复发的高比率，并且通常是恶性的。 对放疗和化疗有抵抗力。这些特点， 归因于未分化的胶质母细胞瘤肿瘤起始细胞或胶质母细胞瘤的存在 干细胞样肿瘤起始细胞（GSC）。最近的研究表明，N6- 甲基腺苷（m6 A）RNA修饰对分化有抗性，并且怀疑它是 可逆性m6 A通路的失调可能在产生肿瘤启动因子中起作用。 细胞和促进肿瘤发生。ALKBH 5表达在原发性和已建立的 GBM细胞富含GSC，高表达与GBM预后不良相关 患者该提案的目的是鉴定和开发新的RNA抑制剂， 脱甲基酶烷基化修复同源蛋白5（ALKBH 5）作为潜在的化疗剂 多形性胶质母细胞瘤我们的项目有三个目标。目标1：优化潜在客户， 通过合理的药物设计选择性抑制ALKBH 5。目的2：建立酶法和 ALKBH 5抑制剂的细胞作用机制。目的3：建立ALKBH 5抑制剂作为 GSC中有效的抗增殖剂。这项工作的预期成果是一个化学 第一批ALKBH 5抑制剂的不同组合。该项目将产生明显的积极影响， 为开发ALKBH 5靶向治疗GBM提供了重要的基础。

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.