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New synthetic inhibitors of fatty acid synthase with anticancer activity.

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
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Jun 14, 2012
Volume
55
Issue
11
Pages
5013–5023
Identifiers
DOI: 10.1021/jm2016045
PMID: 22559865
Source
Medline
License
Unknown

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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