Targeting ATG4B to Treat Glioblastoma

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。

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.