Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency
Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency
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DOI：
10.1073/pnas.1118193109
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发表时间：
2012-05-22
影响因子：
11.1
通讯作者：
Amaravadi, Ravi K.
中科院分区：
文献类型：
--
作者：
McAfee, Quentin;Zhang, Zhihui;Amaravadi, Ravi K.
自噬是一种溶酶体依赖性降解过程，可保护癌细胞免受多种应激。在临床前模型中，氯喹（CQ）衍生物的自噬抑制增强了许多抗癌疗法的疗效，但CQ作为单一药物的活性有限。临床试验正在进行中，将抗癌药物与羟氯喹（HCQ）结合，但抑制自噬所需的HCQ浓度在临床上并不一致。我们报道了双氨基喹啉自噬抑制剂的合成和表征，其有效地抑制自噬并损害体内肿瘤生长。与CQ相比，改善自噬抑制所必需的结构基序包括两个氨基喹啉环和三胺接头和C-7氯的存在。先导化合物Lys 01是比HCQ强10倍的自噬抑制剂。与HCQ相比，Lys 01的水溶性盐Lys 05更有效地在溶酶体内积累并使溶酶体脱酸，导致自噬和肿瘤生长受损。在给予的最高剂量下，一些小鼠发生潘氏细胞功能障碍，其类似于自噬基因ATG 16 L1中具有遗传缺陷的小鼠和人类的肠道表型，提供了Lys 05靶向自噬的体内证据。与HCQ不同，在用较低剂量的Lys 05治疗的小鼠中观察到显著的单药抗肿瘤活性而没有毒性，从而确立了该化合物在癌症中的治疗潜力。
Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.