Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

• DOI: 10.1073/pnas.1118193109
• Publication Date: 2012-05-08T07:17:40Z
• Authors: Quentin McAfee; Zhihui Zhang; Arabinda Samanta; Samuel M. Levi; Xiao-Hong Ma; Shengfu Piao; John P. Lynch; Takeshi Uehara; Antonia R. Sepulveda; Lisa E. Davis; Jeffrey D. Winkler; Ravi K. Amaravadi
• Keywords: ATG16L1

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 single agent. Clinical trials are underway combining agents hydroxychloroquine (HCQ), concentrations HCQ required to inhibit not consistently achievable in clinic. We report synthesis and characterization bisaminoquinoline inhibitors potently impair tumor growth vivo. The structural motifs necessary for improved compared include presence two aminoquinoline rings triamine linker C-7 chlorine. lead compound, Lys01, 10-fold more potent inhibitor than HCQ. Compared HCQ, Lys05, water-soluble salt accumulates within deacidifies lysosome, resulting impaired growth. At highest dose administered, some mice develop Paneth cell dysfunction resembles intestinal phenotype humans genetic defects gene ATG16L1, providing vivo evidence Lys05 targets autophagy. Unlike significant single-agent antitumor observed without toxicity treated lower doses establishing therapeutic potential this compound cancer.