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: 10133170
• 负责人: Luke Lee Lairson
• 金额: $ 53.46万
• 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/10133170
• 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; aggressive therapy; 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 胶质母细胞瘤癌症干细胞（GBM CSC）的存在，以及它们在 GBM肿瘤倡议和疾病进展已清楚地证明和表征。然而， 选择性地针对该细胞群体和围绕潜在治疗靶标的知识的特工是 拼命缺乏。 GBM代表了脑癌的最常见和侵略性形式，目前 仍然是一种几乎无法治愈的疾病。肿瘤维持，脑部浸润，耐药性和复发性 手术后都归因于GBM CSC人群。该项目的长期目标是确定 新目标，机制和潜在的候选药物用于治疗GBM GBM CSC中的细胞凋亡以细胞类型选择的方式。从完整的基于化学遗传学的屏幕 〜100万种药物样小分子，一种新型化合物系列，以称为ripGBM的化合物为例 被鉴定出来的，基于 一系列GBM CSC和非固定细胞类型的分析。这个系列的选择性是 确定是从GBM CSC中RIPGBM的选择性激活得出的，这导致了A的形成 通过与新型蛋白质靶标-RIPK2结合诱导凋亡的物种。总体目标 建议将充分阐明RIPGBM化合物系列的作用机理，以优化其 选择性和效能特性，并在相关的啮齿动物GBM肿瘤中证明抗肿瘤活性 模型。推动该提议的中心假设是，针对RIPK2的小分子前药 在GBM CSC中有选择地激活，以细胞类型选择的方式诱导凋亡，并降低 GBM肿瘤模型中的肿瘤伯嫩。为了实现该提议的总体目标，以下三个 具体目标将成功完成：1A）确定选择性RIPGBM前药的机制 GBM CSC中的激活。 1b）确定CRIPGBM与RIPK2相互作用的结构基础 诱导凋亡。 2）确定RIPGBM的大脑渗透类似物，具有提高的效力和选择性 特性。 3）确定使用患者 - 衍生的GBM CSC基于颅内肿瘤特征模型。工作的结果是 提议将是重要的，因为他们将有助于确定治疗的药物开发候选者 GBM。此外，他们将验证一种新型的可吸毒蛋白靶标的诱导凋亡，并将确定 GBM CSC中选择性前药激活的新机制。