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Publication - Article


Inhibition of the Thioesterase Activity of Human Fatty Acid Synthase by 1,4- and 9,10-Diones



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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 inmany cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to haltproliferation and induce cell death in vitro and to block tumor growth in vivo. Consequently, FASN is widelyrecognized 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 potentlyinhibit the thioesterase (TE) domain of FASN. Inhibition of recombinant TE activity, inhibition of cellularFASN, and cytotoxicity in human prostate cancer cell lines and normal fibroblasts, is shown for the mostpotent inhibitors. Collectively, the data illustrate the novel inhibitory capacity of the 1,4-quinone and 9,10-anthraquinone pharmacophores against FASN.

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