Lys05 is water soluble salt of Lys01. Lys05 shows potent antitumor activity as a single agent both in vitro and in vivo in multiple human cancer cell lines and xenograft models.
Autophagy, the sequestration of organelles and proteins in autophagic vesicles (AVs) and degradation of this cargo through lysosomal fusion, allows tumor cells to survive metabolic and therapeutic stresses[2]. Lys05, a dimeric chloroquine, is a new lysosomal autophagy inhibitor which more potently accumulates in the lysosome and blocks autophagy compared with hydroxychloroquine (HCQ)[3]. C8161 xenografts matched for tumor size were treated with Lys05 (76 mg/kg; i.p.) for 48 h . Cells with intact nuclear and cytoplasmic membranes contained large AVs in Lys05-treated tumors. Meanwhile, significantly higher LC3II/LC3I levels were observed in Lys05-treated tumors compared with control- or HCQ-treated tumors, providing further evidence of in vivo autophagy inhibition. Mice bearing 1205Lu xenografts matched for tumor volume were treated with Lys05 (76 mg/kg; i.p.) and dosed for 3 d of daily treatment with 2 d off treatment. Lys05 treatment resulted in a 53% reduction in the average daily tumor growth rate compared with vehicle-treated controls. A significant six-fold accumulation of AV was observed at the end of 14 d of treatment in Lys05-treated tumors, compared with control group. Extensive tumor necrosis was observed in Lys05-treated tumors[2].
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