Lys05, or Lys01 trihydrochloride, is a potent, water soluble lysosomal autophagy inhibitor. Lys05 is a previously undescribed dimeric chloroquine which more potently accumulates in the lysosome and blocks autophagy compared with HCQ. Lys05 produced more potent antitumor activity as a single agent both in vitro and in vivo in multiple human cancer cell lines and xenograft models compared with HCQ. Lys05 is therefore a new lysosomal autophagy inhibitor that has potential to be developed further into a drug for cancer and other medical applications.

LN229:6μM, 1205Lu:3.6μM, HT29 cells:7.9 μM, C8161 cells:3.8μM

Lys01比HCQ的自噬抑制活性高出10倍。与HCQ相比，其水溶性盐Lys05在溶酶体内的积累能力更强，并且更有效地去酸化溶酶体。Lys01及lys01 trihydrochloride 均能等效地剂量依赖性增加LC3II/LC3I比率，促进自噬载体蛋白p62的积累，并且在MTT实验中展现出相同的IC50值[1]。

在此高剂量短期治疗下，尽管没有小鼠死亡，但在投药2天后，接受Lys05 76 mg/kg i.p.治疗的小鼠出现背部拱起和嗜睡的现象。从形态学上看，电子显微镜显示，Lys05处理的肿瘤中，具有完整核膜和细胞质膜的细胞含有大量自噬囊泡(AVs)。Lys05处理的肿瘤与对照组相比，肿瘤生长显著受阻。与对照组相比，Lys05治疗导致平均每日肿瘤生长率降低53%。在治疗14天末，与对照组相比，HCQ和Lys05处理的肿瘤分别观察到自噬囊泡积累的显著增加，分别是三倍和六倍[1]。

1205Lu, c8161, LN229 and HT-29 cells are treated with lys01 trihydrochloride (0, 0.01, 0.1, 1, and 10 μM) or Lys01 (0, 0.01, 0.1, 1, and 10 μM) in five replicates for 72 h. The Acid Phsophatase Assay kit is used for the MTT assay[1].