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Targeting ATG4B to Treat Glioblastoma

靶向 ATG4B 治疗胶质母细胞瘤

基本信息

批准号：
10605245
负责人：
Shi-Yuan Cheng
金额：
$ 19.25万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605245
关键词：
ATG3 gene Accounting Adjuvant Therapy Adult Animals Attenuated Autophagocytosis Autophagosome Binding Biological Assay Blood - brain barrier anatomy Brain Brain Glioblastoma C-terminal Caspase Cell Proliferation Cell Survival Cell membrane Cells Cellular Stress Central Nervous System Neoplasms Characteristics Chemicals Chemotherapy and/or radiation Common Neoplasm Cysteine Proteinase Inhibitors Development Diagnosis Disease Drug Compounding Enzyme Inhibition Evaluation Frequencies Glioblastoma Glioma Glycine Growth Homeostasis Human In Vitro Investigation Lead Life Malignant - descriptor Malignant Neoplasms Malignant neoplasm of central nervous system Mediating Metabolic Modality Molecular Molecular Biology Nervous System Nude Mice Organic Synthesis Patients Peptide Hydrolases Performance Permeability Pharmaceutical Preparations Phosphatidylethanolamine Phosphorylation Phosphotransferases Play Process Prognosis Protein Isoforms Proteins Radiation therapy Recycling Resistance Role Serine Signal Transduction Therapeutic Toxic effect Translating Tumorigenicity United States Validation Xenograft Model antitumor effect blood-brain barrier permeabilization chemotherapy combat cytotoxicity high reward high risk improved in silico in vivo inhibition of autophagy inhibitor knock-down mouse model neoplastic cell novel radiation response small hairpin RNA small molecule inhibitor standard care standard of care stem-like cell temozolomide therapeutic target tool tumor tumor growth tumor initiation tumor metabolism tumor progression tumor xenograft

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is among the most common and malignant tumor in the central nervous system with an extremely poor prognosis. New treatments for this disease are desperately needed and the protease ATG4B is a new potential target to reduce GBM tumorgenicity and prolong patient life. Based on strong preliminary results, we propose to create new ATG4B inhibitors through a collaborative and iterative process. Our collaborative workflow involves a) optimization of a commercial compound (NSC185058) with poor potency and drug like characteristics guided by in vitro potency and selectivity, b) evaluation of blood brain barrier and metabolic performance, and lastly, c) in vivo efficacy investigations combining our best candidates with radiotherapy and temozolomide. This high risk, high reward project will add validation to ATG4B as a prime target for GBM treatment and provide new Northwestern-based drug compounds to combat this dreaded disease.

项目摘要胶质母细胞瘤（GBM）是中枢神经系统最常见的恶性肿瘤之一，预后极差这种疾病的新疗法是迫切需要的，蛋白酶 ATG4B是降低GBM致瘤性和延长患者生命的新的潜在靶点。基于强初步结果，我们建议通过协作和迭代来创建新的ATG4B抑制剂。过程我们的协作工作流程包括a）优化商业化合物（NSC185058）具有差的效力和由体外效力和选择性指导的药物样特征，B）评价血脑屏障和代谢性能，以及最后，c）结合我们的放疗和替莫唑胺的最佳选择。这个高风险、高回报的项目将增加验证将ATG4B作为GBM治疗的主要靶点，并提供新的基于西北地区的药物化合物，对抗这种可怕的疾病。