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 <b>5</b>–<b>30</b> 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 μM have been tested for their ability to inhibit FASN activity. Among them, derivative <b>30</b> 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, <b>30</b> 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 <b>30</b> may aid the validation of this enzyme as a therapeutic target for the treatment of cancer

A Positive Allosteric Modulator of the Serotonin 5‑HT_2C Receptor for Obesity

The 5-HT_2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT_2CR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues <b>6</b>–<b>41</b> afforded compound <b>11</b> (<i>N</i>-[(1-benzyl-1<i>H</i>-indol-3-yl)­methyl]­pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands. PAM <b>11</b> was very active in feeding inhibition in rodents, an effect that was not related to the activation of 5-HT_2AR. A combination of <b>11</b> with the SSRI sertraline increased the anorectic effect. Subchronic administration of <b>11</b> reduced food intake and body weight gain without causing CNS-related malaise. The behavior of compound <b>11</b> identified in this work supports the interest of a serotonin 5-HT_2CR PAM as a promising therapeutic approach for obesity