RT Journal Article
SR Electronic
T1 Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency
JF Proceedings of the National Academy of Sciences
JO Proc Natl Acad Sci USA
FD National Academy of Sciences
SP 8253
OP 8258
DO 10.1073/pnas.1118193109
VO 109
IS 21
A1 McAfee, Quentin
A1 Zhang, Zhihui
A1 Samanta, Arabinda
A1 Levi, Samuel M.
A1 Ma, Xiao-Hong
A1 Piao, Shengfu
A1 Lynch, John P.
A1 Uehara, Takeshi
A1 Sepulveda, Antonia R.
A1 Davis, Lisa E.
A1 Winkler, Jeffrey D.
A1 Amaravadi, Ravi K.
YR 2012
UL http://www.pnas.org/content/109/21/8253.abstract
AB 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.