title: New synthetic inhibitors of fatty acid synthase with anticancer activity.
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.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Turrado
authors.forename: Teresa
authors.initials: T
authors.lastname: Puig
authors.forename: Javier
authors.initials: J
authors.lastname: García-Cárceles
authors.forename: Marta
authors.initials: M
authors.lastname: Artola
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Joana
authors.initials: J
authors.lastname: Relat
authors.forename: Gloria
authors.initials: G
authors.lastname: Oliveras
authors.forename: Adriana
authors.initials: A
authors.lastname: Blancafort
authors.forename: Diego
authors.initials: D
authors.lastname: Haro
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Marrero
authors.forename: Ramón
authors.initials: R
authors.lastname: Colomer
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D059808:Polyphenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D059808:Polyphenols; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human