Inhibitors of Fatty Acid Synthase for Prostate Cancer. Revision

摘要

Fatty acid synthase (FASN), the enzyme that synthesizes fatty acid in cells, is over-expressed in prostate cancer and a potential therapeutic target. We have identified several novel chemical scaffolds with potential to inhibit FASN, from several hundred compounds discovered and synthesized by us. An extensive series of compounds with anti-FASN properties have been synthesized and characterized for their ability to inhibit recombinant FASN, FASN activity in tumor cells, and to kill prostate cancer cell lines. The best inhibitors have increased potency over other FASN inhibitors, including orlistat, the prototype FASN thioesterase inhibitor. There are solubility issues with some compounds, decreasing delivery and effectiveness. The low solubility is likely due to the hydrophobic nature of the TE domain, owing to the fact that is recognized saturated fat as a substrate. This report summarizes the immense amount of structure-activity-relationships for new compounds we developed and reports on a new click-chemistry approach to derive novel FASN inhibitors.