New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity

Abstract

Fatty acid synthase (FASN) is a lipogenic enzyme that is highly expressed in different human cancers. Here we report the development of a new series of polyphenolic compounds 5-30 that have been evaluated for their cytotoxic capacity in SK-Br3 cells, a human breast cancer cell line with high FASN expression. The compounds with an IC(50) < 50 μM have been tested for their ability to inhibit FASN activity. Among them, derivative 30 blocks the 90% of FASN activity at low concentration (4 μM), is highly cytotoxic in a broad panel of tumor cells, induces apoptosis, and blocks the activation of HER2, AKT, and ERK pathways. Remarkably, 30 does not activate carnitine palmitoyltransferase-1 (CPT-1) nor induces in mice weight loss, which are the main drawbacks of other previously described FASN inhibitors. Thus, FASN inhibitor 30 may aid the validation of this enzyme as a therapeutic target for the treatment of cancer.

Metformin-Induced Killing of Triple-Negative Breast Cancer Cells Is Mediated by Reduction in Fatty Acid Synthase via miRNA-193b

“…Silencing of ACACA or FASN kills breast cancer cells while non-transformed human breast epithelial cells are unaffected [7], confirming the importance of lipogenesis in cancer cell survival [8]. These observations suggest that de novo fatty acid synthesis provides a survival advantage to tumor cells and the possibility that FASN could serve as a target for anti-cancer therapeutics [6, 9–12]. …”

(−)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

“…Buffer pH = 7 and NH 4 Cl sat. at 0ºC were slowly added, and the mixture was stirred for 15 min at 0ºC and 10 min at r.t.…”

“…FAS catalyses fatty acid synthesis from the substrates acetylCoA and malonyl-CoA [3]. There is increased interest in finding novel FAS inhibitors as antitumor drugs and many compounds have been evaluated for their cytotoxic capacity [4,5]. Among them, C75 is a chemically stable inhibitor of FAS that binds to the enzyme and inhibits its activity [6].…”

Crystal Structure of the Human Fatty Acid Synthase Enoyl-Acyl Carrier Protein-Reductase Domain Complexed with Triclosan Reveals Allosteric Protein-Protein Interface Inhibition

“…Its relationship with cancer pathogenesis has attracted the most attention (9,10). In humans, diet is the primary source of fatty acids, and FAS is expressed at very low levels.…”