| Reference | 1. Autophagy. 2012 Sep;8(9):1383-4. doi: 10.4161/auto.20958. Epub 2012 Aug 10. <br />
<br />
Lys05: a new lysosomal autophagy inhibitor. <br />
<br />
Amaravadi RK(1), Winkler JD. <br />
Author information: <br />
(1)Department of Medicine, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA. [email protected] <br />
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.
Initial structure-activity relationship studies demonstrated that the increased
activity associated with Lys05 was due to the bivalent aminoquinoline rings,
C7-Chlorine, and a short triamine linker. While lower doses of Lys05 were well
tolerated and associated with antitumor activity, at the highest dose tested,
Lys05 produced Paneth cell dysfunction and intestinal toxicity, similar to what
can be observed in mice and humans with genetic defects in the autophagy gene
ATG16L1. Lys05 is therefore a new lysosomal autophagy inhibitor that has
potential to be developed further into a drug for cancer and other medical
applications. <br />
<br />
2. Proc Natl Acad Sci U S A. 2012 May 22;109(21):8253-8. doi:
10.1073/pnas.1118193109. Epub 2012 May 7. <br />
<br />
Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the
phenotype of a genetic autophagy deficiency. <br />
<br />
McAfee Q(1), Zhang Z, Samanta A, Levi SM, Ma XH, Piao S, Lynch JP, Uehara T,
Sepulveda AR, Davis LE, Winkler JD, Amaravadi RK. <br />
Author information: <br />
(1)Department of Medicine, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA 19104, USA. <br />
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. <br />
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