{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:57:39Z","timestamp":1791352659756,"version":"4.3.1"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"21","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,5,22]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>ATG16L1<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1118193109","type":"journal-article","created":{"date-parts":[[2012,5,8]],"date-time":"2012-05-08T03:17:40Z","timestamp":1336447060000},"page":"8253-8258","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":390,"title":["Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency"],"prefix":"10.1073","volume":"109","author":[{"given":"Quentin","family":"McAfee","sequence":"first","affiliation":[{"name":"Departments of aMedicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Arts and Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arabinda","family":"Samanta","sequence":"additional","affiliation":[{"name":"Departments of aMedicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel M.","family":"Levi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Arts and Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hong","family":"Ma","sequence":"additional","affiliation":[{"name":"Departments of aMedicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengfu","family":"Piao","sequence":"additional","affiliation":[{"name":"Departments of aMedicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Departments of aMedicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Uehara","sequence":"additional","affiliation":[{"name":"Pathology, Perelman School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia R.","family":"Sepulveda","sequence":"additional","affiliation":[{"name":"Pathology, Perelman School of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa E.","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice &amp; Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Winkler","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Arts and Sciences, and"},{"name":"Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi K.","family":"Amaravadi","sequence":"additional","affiliation":[{"name":"Departments of aMedicine and"},{"name":"Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,5,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1660"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-1595"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28833"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.06.001"},{"key":"e_1_3_3_5_2","first-page":"3837","article-title":"Autophagy-induced tumor dormancy in ovarian cancer","volume":"118","author":"Amaravadi RK","year":"2008","unstructured":"RK Amaravadi, Autophagy-induced tumor dormancy in ovarian cancer. 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