Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase

Kristy Koselny; Julianne Green; Lacey Favazzo; Virginia E Glazier; Louis DiDone; Shea Ransford; Damian J Krysan

doi:10.1021/acsinfecdis.5b00134

Back

Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase

Journal article

Open access

Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase

Kristy Koselny, Julianne Green, Lacey Favazzo, Virginia E Glazier, Louis DiDone, Shea Ransford and Damian J Krysan

ACS infectious diseases, Vol.2(4), pp.268-280

04/08/2016

DOI: 10.1021/acsinfecdis.5b00134

PMCID: PMC4828684

PMID: 27088128

Files and links (1)

url

https://doi.org/10.1021/acsinfecdis.5b00134View

Published (Version of record) Open Access

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.

antifungal

acetyl CoA synthetase

chemical genetics

C. albicans

Details

Title: Subtitle: Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase
Creators: Kristy Koselny - Department of Pediatrics and
Julianne Green - Department of Pediatrics and
Lacey Favazzo - Department of Pediatrics and
Virginia E Glazier - Department of Pediatrics and
Louis DiDone - Department of Pediatrics and
Shea Ransford - Department of Pediatrics and
Damian J Krysan - Department of Pediatrics and
Resource Type: Journal article
Publication Details: ACS infectious diseases, Vol.2(4), pp.268-280
DOI: 10.1021/acsinfecdis.5b00134
PMID: 27088128
PMCID: PMC4828684
NLM abbreviation: ACS Infect Dis
ISSN: 2373-8227
eISSN: 2373-8227
Publisher: American Chemical Society
Grant note: DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: 1R01AI097142, N01-AI-60011; DOI: 10.13039/100000071, name: National Institute of Child Health and Human Development, award: 5K12HD068373
Language: English
Date published: 04/08/2016
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093232402771

Metrics

29 Record Views

49 Times Cited - Web of Science