New synthetic inhibitors of fatty acid synthase with anticancer activity

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.