title: Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency.
abstract: 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.
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Quentin
authors.initials: Q
authors.lastname: McAfee
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Arabinda
authors.initials: A
authors.lastname: Samanta
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Levi
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Ma
authors.forename: Shengfu
authors.initials: S
authors.lastname: Piao
authors.forename: John P
authors.initials: JP
authors.lastname: Lynch
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uehara
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Davis
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Winkler
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071183:Autophagy-Related Proteins; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology; D007415:Intestinal Obstruction / Q000139:chemically induced / Q000235:genetics; D008247:Lysosomes / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D011073:Polyamines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
chemical_list: C518959:ATG16L1 protein, human; D000634:Aminoquinolines; D000962:Antimalarials; D000970:Antineoplastic Agents; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C573930:Lys01; D011073:Polyamines; D006886:Hydroxychloroquine