New synthetic inhibitors of fatty acid synthase with anticancer activity |
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Authors: | Turrado Carlos Puig Teresa García-Cárceles Javier Artola Marta Benhamú Bellinda Ortega-Gutiérrez Silvia Relat Joana Oliveras Gloria Blancafort Adriana Haro Diego Marrero Pedro F Colomer Ramón López-Rodríguez María L |
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Affiliation: | Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain. |
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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. |
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