title: Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase.
abstract: AR-12/OSU-03012 is an antitumor celecoxib-derivative that has progressed to Phase I clinical trial as an anticancer agent and has activity against a number of infectious agents including fungi, bacteria and viruses. However, the mechanism of these activities has remained unclear. Based on a chemical-genetic profiling approach in yeast, we have found that AR-12 is an ATP-competitive, time-dependent inhibitor of yeast acetyl coenzyme A synthetase. AR-12-treated fungal cells show phenotypes consistent with the genetic reduction of acetyl CoA synthetase activity, including induction of autophagy, decreased histone acetylation, and loss of cellular integrity. In addition, AR-12 is a weak inhibitor of human acetyl CoA synthetase ACCS2. Acetyl CoA synthetase activity is essential in many fungi and parasites. In contrast, acetyl CoA is primarily synthesized by an alternate enzyme, ATP-citrate lyase, in mammalian cells. Taken together, our results indicate that AR-12 is a non-nucleoside acetyl CoA synthetase inhibitor and that acetyl CoA synthetase may be a feasible antifungal drug target.
authors.affiliation: Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue, Rochester, New York 14642, United States.
authors.forename: Kristy
authors.initials: K
authors.lastname: Koselny
authors.affiliation: Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue, Rochester, New York 14642, United States.
authors.forename: Julianne
authors.initials: J
authors.lastname: Green
authors.affiliation: Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue, Rochester, New York 14642, United States.
authors.forename: Lacey
authors.initials: L
authors.lastname: Favazzo
authors.affiliation: Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue, Rochester, New York 14642, United States.
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Glazier
authors.affiliation: Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue, Rochester, New York 14642, United States.
authors.forename: Louis
authors.initials: L
authors.lastname: DiDone
authors.affiliation: Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue, Rochester, New York 14642, United States.
authors.forename: Shea
authors.initials: S
authors.lastname: Ransford
authors.affiliation: Department of Pediatrics and Department of Microbiology/Immunology, University of Rochester School of Medicine and Dentistry , 601 Elmwood Avenue, Rochester, New York 14642, United States.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Krysan
keywords: C. albicans; acetyl CoA synthetase; antifungal; chemical genetics