New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity

详细信息    查看全文

• 作者：Carlos Turrado ; Teresa Puig ; Javier Garc铆a-C谩rceles ; Marta Artola ; Bellinda Benham煤 ; Silvia Ortega-Guti茅rrez ; Joana Relat ; Gloria Oliveras ; Adriana Blancafort ; Diego Haro ; Pedro F. Marrero ; Ram贸n Colomer ; Mar铆a L. L贸pez-Rodr铆guez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5013-5023
• 全文大小：415K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

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鈥?b>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 渭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 渭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.