A RIPK2-Targeting Apoptosis-Inducing Small Molecule for the Treatment of Glioblastoma

用于治疗胶质母细胞瘤的 RIPK2 靶向凋亡诱导小分子

• 批准号: 9803569
• 负责人: Luke Lee Lairson
• 金额: $ 55.79万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803569
• 关键词: Achievement; Affinity; Apoptosis; Apoptotic; Automobile Driving; Binding; Brain; Brain Hypoxia-Ischemia; Cells; Chemicals; Data; Development; Disease; Disease Progression; Dose; Electrons; Enzymes; Glioblastoma; Glioma; Goals; Infiltration; Inflammatory; Intracranial Neoplasms; Knowledge; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Mass Spectrum Analysis; Modeling; Modification; Molecular Target; Mus; Naphthoquinones; Nitrogen; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Population; Prodrugs; Property; Proteins; Recurrence; Resistance; Rodent; Role; Series; Signal Transduction; Structure; Survival Rate; Testing; Tumor Burden; Ubiquitination; Work; Xenograft Model; analog; base; cancer stem cell; cell growth; cell type; chemical genetics; drug candidate; drug development; effective therapy; efficacy study; improved; in vivo; lead candidate; neoplastic cell; neuron loss; novel; receptor; selective expression; small molecule; stem-like cell; therapeutic target; treatment strategy; tumor; tumor initiation; virtual

Project Summary/Abstract The existence of glioblastoma cancer stem cells (GBM CSCs), as well as the causative role that they play in GBM tumor initiation and disease progression, has been clearly demonstrated and characterized. However, agents that selectively target this cell population and knowledge surrounding potential therapeutic targets are desperately lacking. GBM represents the most common and aggressive form of brain cancer and, at present, remains a virtually incurable disease. Tumor maintenance, brain infiltration, therapy resistance and recurrence following surgery are all attributed to GBM CSC populations. The long-term goal of this project is to identify new targets, mechanisms and potential drug candidates for the treatment of GBM, which function to induce apoptosis in GBM CSCs in a cell type-selective manner. From a completed chemical genetics-based screen of ~1 million drug-like small molecules, a novel compound series, exemplified by a compound termed RIPGBM, was identified that was found to induce apoptosis in GBM CSCs with unparalleled selectivity, based on the profiling of a broad panel of GBM CSCs and non-diseased cell types. The selectivity of this series was determined to be derived from selective activation of RIPGBM in GBM CSCs, which leads to the formation of a species that induces apoptosis by binding to a novel protein target – RIPK2. The overall objectives of this proposal are to fully elucidate the mechanism of action of the RIPGBM compound series, to optimize its selectivity and potency properties and to demonstrate anti-tumor activity in a relevant rodent GBM tumor model. The central hypothesis driving this proposal is that RIPK2-targeting small molecule prodrugs, which become selectively activated in GBM CSCs, induce apoptosis in a cell type-selective manner and reduce tumor burden in GBM tumor models. To achieve the overall objective of this proposal, the following three specific aims will be successfully completed: 1A) Determine the mechanism of selective RIPGBM prodrug activation in GBM CSCs. 1B) Determine the structural basis by which the interaction of cRIPGBM with RIPK2 induces apoptosis. 2) Identify brain penetrant analogs of RIPGBM with improved potency and selectivity properties. 3) Determine the disease modifying activity of an optimal RIPGBM lead candidate, using a patient- derived GBM CSC-based orthotopic intracranial tumor xenograft model. The results of the work being proposed will be significant, as they will serve to identify a drug development candidate for the treatment of GBM. Additionally, they will validate a novel druggable protein target for induced apoptosis and will identify a new mechanism for selective prodrug activation in GBM CSCs.

项目摘要/摘要 胶质母细胞瘤肿瘤干细胞(GBM CSCs)的存在及其在 GBM肿瘤的发生和疾病的进展，已经被清楚地证明和描述。然而， 选择性地针对这些细胞群体和围绕潜在治疗靶点的知识的药物是 极度缺乏。基底膜是最常见和最具侵袭性的脑癌，目前， 实际上仍然是一种不治之症。肿瘤维持、脑浸润、治疗抵抗和复发 手术后的所有病例都归因于GBM CSC人群。该项目的长期目标是确定 治疗GBM的新靶点、机制和潜在的候选药物，其功能是诱导 GBM CSCs中细胞类型选择性的凋亡。来自完整的基于化学遗传学的筛查 ~100万个类药物小分子，一个新的化合物系列，以一种名为RIPGBM的化合物为例， 被发现以无与伦比的选择性诱导GBM CSCs凋亡，基于 对广泛的GBM CSCs和非病变细胞类型进行分析。这个系列的选择性是 确定源于GBM CSCs中RIPGBM的选择性激活，导致形成 通过与新的蛋白质靶标-RIPK2结合来诱导细胞凋亡的物种。这个项目的总体目标是 建议充分阐明RIPGBM化合物系列的作用机理，优化其 相关啮齿动物GBM肿瘤的选择性和效力特性及其抗肿瘤活性 模特。支持这一提议的中心假设是RIPK2靶向小分子前体药物，这 在GBM CSCs中选择性激活，以细胞类型选择性的方式诱导细胞凋亡，并减少 GBM肿瘤模型中的肿瘤负荷。为了实现这项建议的总体目标，以下三个方面 具体目标将顺利完成：1)确定选择性RIPGBM前药的作用机制 在GBM CSCs中的激活。1b)确定cRIPGBM与RIPK2相互作用的结构基础 诱导细胞凋亡。2)识别具有更高效力和选择性的RIPGBM的脑渗透类似物 属性。3)确定最佳RIPGBM候选领导的疾病修改活性，使用患者- 衍生的基于GBM-CSC的颅内肿瘤原位移植模型。工作的结果是 建议将具有重大意义，因为它们将有助于确定治疗该病的药物开发候选者 GBM。此外，他们将验证一种用于诱导细胞凋亡的新的可药物蛋白靶标，并将确定一种 GBM CSCs选择性前药激活的新机制。