title: Synthesis of improved lysomotropic autophagy inhibitors.
abstract: Autophagy is a conserved cellular pathway used to recycle nutrients through lysosomal breakdown basally and under times of stress (e.g., nutrient deprivation, chemotherapeutic treatment). Oncogenes are known to induce autophagy, which may be exploited by cancers for cell survival. To identify autophagy inhibitors with potential therapeutic value for cancer, we screened a panel of antimalarial agents and found that quinacrine (QN) had 60-fold higher potency of autophagy inhibition than chloroquine (CQ), a well-known autophagy inhibitor that functions by disrupting lysosomal activity. Despite desirable autophagy inhibiting properties, QN showed considerable cytotoxicity. Therefore, we designed and synthesized a novel series of QN analogs and investigated their effects on autophagy inhibition and cell viability. Notably, we found two compounds (33 and 34), bearing a backbone of 1,2,3,4-tetrahydroacridine, had limited cytotoxicity yet strong autophagy inhibition properties. In conclusion, these improved lysomotropic autophagy inhibitors may have use as anticancer agents in combination with conventional therapies.
authors: †Translational Drug Development (TD2, LLC), Scottsdale, Arizona 85259, United States.
authors: Tong
authors: T
authors: Wang
authors: ‡Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, United States.|§Genetics Graduate Program, Michigan State University, East Lansing, Michigan 48824, United States.
authors: Megan L
authors: ML
authors: Goodall
authors: †Translational Drug Development (TD2, LLC), Scottsdale, Arizona 85259, United States.
authors: Paul
authors: P
authors: Gonzales
authors: †Translational Drug Development (TD2, LLC), Scottsdale, Arizona 85259, United States.
authors: Mario
authors: M
authors: Sepulveda
authors: ‡Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, United States.
authors: Katie R
authors: KR
authors: Martin
authors: †Translational Drug Development (TD2, LLC), Scottsdale, Arizona 85259, United States.
authors: Stephen
authors: S
authors: Gately
authors: ‡Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, United States.
authors: Jeffrey P
authors: JP
authors: MacKeigan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011796:Quinacrine / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D002738:Chloroquine; D011796:Quinacrine