Development of lysosome targeted therapeutics

项目总结/摘要 溶酶体蛋白水解促进细胞器和选择的长寿命蛋白的周转，并且是一个关键的 细胞内环境稳定的调节器。其异常活化通过以下方式促进耐药性和癌症进展： 为缺氧应激的细胞产生维持生存的代谢燃料的替代来源， 放疗、化疗和靶向药物。尽管它作为治疗靶点的潜力很明显，但没有人有意地 迄今为止，设计的溶酶体功能靶向抑制剂已被FDA批准。我们最近生成了一个 一系列新型口服溶酶体破坏剂，具有良好的安全性和单药 治疗活性。我们的第一个铅击中是积极对急性髓细胞白血病（AML）细胞的高风险特征 并增强阿扎胞苷的功效，显着延长急性髓细胞白血病小鼠模型的总生存期。我们 主要目标是使用药物化学方法优化其药理学特性，以开发一种新的 溶酶体蛋白水解抑制剂，其可以商业化用于治疗AML和其他疾病的患者。 异常途径活性导致发病的疾病。

Project Summary/Abstract Lysosomal proteolysis facilitates the turnover of organelles and selected long-lived proteins and is a critical regulator of cellular homeostasis. Its aberrant activation promotes drug resistance and cancer progression by generating alternative sources of survival sustaining metabolic fuel to cells that are stressed by hypoxia, radiation, chemotherapy, and targeted agents. Despite its clear potential as a therapeutic target, no intentionally designed targeted inhibitors of lysosomal function have been FDA approved to date. We recently generated a series of novel orally available lysosomal disrupting agents with favorable safety profiles and single agent therapeutic activity. Our first lead hit is active against acute myeloid leukemia (AML) cells with high-risk features and augments the efficacy of azacitidine to significantly extend overall survival in mouse models of AML. Our major goal is to use medicinal chemistry approaches to optimize its pharmacologic properties to develop a novel lysosomal proteolysis inhibitor that can be commercialized for the treatment of patients with AML and other diseases where aberrant pathway activity contributes to pathogenesis.