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New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity

2012; American Chemical Society; Volume: 55; Issue: 11 Linguagem: Inglês

10.1021/jm2016045

1520-4804

Carlos Turrado, Teresa Puig, Javier García‐Cárceles, Marta Artola, Bellinda Benhamú, Silvia Ortega‐Gutiérrez, Joana Relat, Glòria Oliveras, Adriana Blancafort, Diego Haro, Pedro F. Marrero, Rámón Colomer, María L. López-Rodrı́guez,

Inflammatory mediators and NSAID effects

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.