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.

项目概要胶质母细胞瘤（GBM）是中枢神经系统最常见的恶性肿瘤之一，预后极差。迫切需要针对这种疾病的新疗法，蛋白酶 ATG4B 是降低 GBM 致瘤性和延长患者生命的新潜在靶点。立足于强根据初步结果，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涉及 a) 商业化合物的优化 (NSC185058) 具有较差的效力和类似药物的特征，以体外效力和选择性为指导，b) 评估血脑屏障和代谢性能，最后，c）结合我们的体内功效研究放疗和替莫唑胺的最佳候选者。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，并提供新的西北药物化合物对抗这种可怕的疾病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting neddylation in cancer.

靶向癌症中的neddylation。

DOI：
发表时间：
2022-11-02
期刊：
影响因子：
15.9
作者：
Goenka, Anshika;Cheng, Shi
通讯作者：
Cheng, Shi

PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines.

PETCH-DB：探索组织特异性和复杂疾病相关 5-羟甲基胞嘧啶的门户。

DOI：
发表时间：
2023-06-10
期刊：
影响因子：
0
作者：
Cai, Qinyun;Zhang, Zhou;Cui, Xiaolong;Zeng, Chang;Cai, Jiabin;Cai, Jiajun;Wu, Kai;Zhang, Xu;Shi, Yixiang;Arvanitakis, Zoe;Bissonnette, Marc A;Chiu, Brian C;Cheng, Shi;He, Chuan;Zhang, Wei
通讯作者：
Zhang, Wei

Unconventional Protein Secretion in Brain Tumors Biology: Enlightening the Mechanisms for Tumor Survival and Progression.

脑肿瘤生物学中的非常规蛋白质分泌：阐明肿瘤生存和进展的机制。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Iglesia, Rebeca Piatniczka;Prado, Mariana Brandão;Alves, Rodrigo Nunes;Escobar, Maria Isabel Melo;Fernandes, Camila Felix de Lima;Fortes, Ailine Cibele Dos Santos;Souza, Maria Clara da Silva;Boccacino, Jacqueline Marcia;Cangiano, Giovanni;Soares
通讯作者：
Soares

Synthesis and Structural Optimization of ATG4B Inhibitors for the Attenuation of Autophagy in Glioblastoma.

用于减弱胶质母细胞瘤自噬的 ATG4B 抑制剂的合成和结构优化。

DOI：
10.1021/acsmedchemlett.3c00505
发表时间：
2024-01-16
期刊：
ACS medicinal chemistry letters
影响因子：
4.2
作者：
Dalton R. Kim;Meghan J. Orr;Xiaozhou Yu;Hasan H. Munshi;Austin Wang;Claire Trudeau;Ada J. Kwong;Shi;Karl A. Scheidt
通讯作者：
Karl A. Scheidt

The mammalian Sterile 20-like kinase 4 (MST4) signaling in tumor progression: Implications for therapy.

哺乳动物不育 20 样激酶 4 (MST4) 信号在肿瘤进展中的作用：对治疗的影响。