急性髓系白血病（AML）是一种异质性的血液系统癌症，特点是预后差和频繁复发。除了与特定突变相关的改变外，在AML中，溶酶体和线粒体的总体功能被大幅改变以满足升高的生物量和能量需求。基于以前的结果，通过计算机筛选药物发现来鉴定一个新的溶酶体/线粒体靶向化合物家族。这些新型四环素化合物，具有阳离子两性结构，通过诱导线粒体损伤和细胞凋亡以及溶酶体膜泄漏而特异地根除白血病细胞。溶酶体泄漏不仅引起典型的溶酶体依赖性细胞死亡，而且还通过Ca2+，TFEB和MYC信号轴激活AML细胞的末端分化。除了是有效的单药疗法外，在其他类型的白血病中使用的化学治疗药物三氧化二砷（ATO）与其联合应用在AML细胞中高度协同作用，扩大了治疗的治疗时间窗口。此外，这些化合物在广泛的癌细胞系中具有良好的药理学特性，使它们成为AML和其他肿瘤治疗的有前途的候选药物。

Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+-TFEB-MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias.