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: 10377492
• 负责人: Luke Lee Lairson
• 金额: $ 52.82万
• 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/10377492
• 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; 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.

项目总结/摘要 胶质母细胞瘤癌症干细胞（GBM CSC）的存在，以及它们在肿瘤中的致病作用， GBM肿瘤的发生和疾病的进展已经得到了明确的证明和表征。然而，在这方面， 选择性靶向该细胞群的药剂和关于潜在治疗靶点的知识， 极度缺乏。GBM代表了脑癌中最常见和最具侵袭性的形式，目前， 仍然是一种几乎无法治愈的疾病。肿瘤维持、脑浸润、治疗抵抗和复发 术后的死亡率均归因于GBM CSC人群。该项目的长期目标是确定 新的目标，机制和潜在的候选药物治疗GBM，其功能是诱导 GBM CSC中的细胞凋亡以细胞类型选择性方式。从一个完整的化学遗传学为基础的筛选， ~ 100万个药物样小分子，一种新的化合物系列，以称为RIPGBM的化合物为例， 发现其以无与伦比的选择性诱导GBM CSC中的凋亡， GBM CSC和非患病细胞类型的广泛组的分析。该系列的选择性为 被确定为来源于GBM CSC中RIPGBM的选择性活化，这导致了GBM CSC中RIPGBM的形成。 通过与新的蛋白质靶点RIPK 2结合诱导细胞凋亡的物种。这一总体目标 建议是充分阐明RIPGBM化合物系列的作用机制，优化其 选择性和效力性质，并证明在相关啮齿动物GBM肿瘤中的抗肿瘤活性 模型推动这一提议的中心假设是RIPK 2靶向小分子前药， 在GBM CSC中被选择性激活，以细胞类型选择性方式诱导凋亡，并减少 GBM肿瘤模型中的肿瘤负荷。为了实现本建议的总体目标， 具体目标将顺利完成：1A）确定选择性RIPGBM前药的作用机制 GBM CSC中的活化。1B）确定cRIPGBM与RIPK 2相互作用的结构基础 诱导细胞凋亡。2)鉴定具有改进的效力和选择性的RIPGBM的脑渗透剂类似物 特性. 3)确定最佳RIPGBM先导候选药物的疾病改善活性，使用患者- 衍生的基于GBM CSC的原位颅内肿瘤异种移植物模型。工作的结果是 这些建议将是重要的，因为它们将用于确定治疗糖尿病的药物开发候选药物。 GBM。此外，他们将验证一种新的可药物化的诱导细胞凋亡的蛋白质靶点，并将确定一种新的靶点。 GBM CSC中选择性前药活化的新机制。