title: Inhibition of the thioesterase activity of human fatty acid synthase by 1,4- and 9,10-diones.
abstract: Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo. Consequently, FASN is widely recognized as a valuable therapeutic target. In this report, we describe a variety of 1,4-quinones and 9,10-anthraquinones, including several natural compounds and some newly synthesized compounds, that potently inhibit the thioesterase (TE) domain of FASN. Inhibition of recombinant TE activity, inhibition of cellular FASN, and cytotoxicity in human prostate cancer cell lines and normal fibroblasts, is shown for the most potent inhibitors. Collectively, the data illustrate the novel inhibitory capacity of the 1,4-quinone and 9,10-anthraquinone pharmacophores against FASN.
authors.affiliation: Department of Biochemistry and Center for Structural Biology, Wake Forest School of Medicine.
authors.forename: Herman
authors.initials: H
authors.lastname: Odens
authors.forename: Todd
authors.initials: T
authors.lastname: Lowther
authors.forename: Steven
authors.initials: S
authors.lastname: Kridel
authors.forename: Laura
authors.initials: L
authors.lastname: Watts
authors.forename: Lauren
authors.initials: L
authors.lastname: Filipponi
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schmitt
mesh_terms: D004950:Esterases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D013438:Sulfhydryl Compounds; D064429:Fatty Acid Synthases; D004950:Esterases