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.

项目总结/文摘