title: Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells.
abstract: The autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) have single agent antiproliferative activity against human cancer cell lines; however, low potency may limit their antitumor efficacy clinically. We synthesized a series of chloroquine analogs that retained the 4-aminoquinoline subunit and incorporated different substituted triazoles into the target structure. These compounds were tested for growth inhibition against H460 and HCC827 human lung cancer and BxPC3 pancreatic cancer cells. The most potent compound, EAD1, had an IC50 of 5.8 μM in the BxPC3 cells and was approximately 8-fold more potent than CQ and HCQ. EAD1 inhibited autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62 and induced apoptosis. The increases in LC3-II levels by the analogues were highly correlated with their growth inhibitory IC50s, suggesting that autophagy blockade is closely linked to inhibition of cell proliferation. EAD1 is a viable lead compound for evaluation of the antitumor activity of autophagy inhibitors in vivo.
authors.affiliation: Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Lars Ulrik
authors.initials: LU
authors.lastname: Nordstrøm
authors.affiliation: Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Juan
authors.initials: J
authors.lastname: Sironi
authors.affiliation: Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Aranda
authors.affiliation: Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Jorge
authors.initials: J
authors.lastname: Maisonet
authors.affiliation: Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Roman
authors.initials: R
authors.lastname: Perez-Soler
authors.affiliation: Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Departments of Biochemistry and Medicine (Oncology), Albert Einstein College of Medicine , Bronx, New York 10461, United States.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Schwartz
keywords: Autophagy; chloroquinoline triazoles; click chemistry; lung cancer; pancreatic cancer