New synthetic inhibitors of fatty acid synthase with anticancer activity
2012
Turrado, Carlos | Puig i Miquel, Teresa | García-Cárceles, Javier | Artola Pino, Marta | Benhamú, Bellinda | Ortega-Gutiérrez, Silvia | Relat Pardo, Joana | Oliveras Serrat, Glòria | Blancafort, Adriana | Haro Bautista, Diego | Marrero González, Pedro F. | Colomer Bosch, Ramón | López-Rodríguez, María Luz
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 IC50 < 50 M have been tested for their ability to inhibit FASN activity. Among them, derivative 30 blocks the 90% of FASN activity at low concentration (4 M), 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.
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