Targeting ATG4B to Treat Glioblastoma

项目总结 胶质母细胞瘤(GBM)是中枢神经系统最常见和最恶性的肿瘤之一， 预后极差。这种疾病迫切需要新的治疗方法，而蛋白酶 ATG4B是降低GBM致瘤性、延长患者生命的新的潜在靶点。基于强大的 初步结果，我们建议通过合作和迭代来创造新的ATG4B抑制剂 进程。我们的协作工作流程涉及a)商业大院(NSC185058)的优化 由体外效力和选择性引导的效力较差和类似药物的特征，b)评价 血脑屏障和代谢表现，最后，c)体内疗效研究结合我们的 接受放射治疗和替莫唑胺治疗的最佳人选。这个高风险、高回报的项目将增加验证 将ATG4B作为治疗GBM的主要靶点，并提供新的基于西北的药物化合物 与这种可怕的疾病作斗争。

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.