Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 11, Pages 5013-5023Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm2016045
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Funding
- Spanish Ministerio de Economia y Competitividad (MINECO) [SAF2010-22198-C02-01, SAF2010-15217, CIT090000-2008-10]
- Spanish Instituto de Salud Carlos III [FIS PI082031]
- Catalan government [2009SGR163]
- Comunidad de Madrid [S2010/BMD-2353]
- Spanish Society of Medical Oncology [SEOM08]
- MINECO
- European Social Fund
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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 art IC50 < 50 mu 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 mu 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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