An Inhibitor of Fatty Acid Synthase Thioesterase Domain with Improved Cytotoxicity against Breast Cancer Cells and Stability in Plasma.

Abstract

It is well recognized that many cancers are addicted to a constant supply of fatty acids (FAs) and exhibit brisk de novo FA synthesis. Upregulation of a key lipogenic enzyme, fatty acid synthase (FASN), is a near-universal feature of human cancers and their precursor lesions, and has been associated with chemoresistance, tumor metastasis, and diminished patient survival. FASN inhibition has been shown to be effective in killing cancer cells, but progress in the field has been hindered by off-target effects and poor pharmaceutical properties of candidate compounds. Our initial hit (compound 1) was identified from a high-throughput screening effort by the Sanford-Burnham Center for Chemical Genomics using purified FASN thioesterase (FASN-TE) domain. Despite being a potent inhibitor of purified FASN-TE, compound 1 proved highly unstable in mouse plasma and only weakly cytotoxic to breast cancer (BC) cells in vitro. An iterative process of synthesis, cytotoxicity testing, and plasma stability assessment was used to identify a new lead (compound 41). This lead is more cytotoxic against multiple BC cell lines than tetrahydro-4-methylene-2S-octyl-5-oxo-3R-furancarboxylic acid (the literature standard for inhibiting FASN), is stable in mouse plasma, and shows negligible cytotoxic effects against nontumorigenic mammary epithelial cells. Compound 41 also has drug-like physical properties based on Lipinski's rules and is, therefore, a valuable new lead for targeting fatty acid synthesis to exploit the requirement of tumor cells for fatty acids. SIGNIFICANCE STATEMENT: An iterative process of synthesis and biological testing was used to identify a novel thioesterase domain FASN inhibitor that has drug-like properties, is more cytotoxic to breast cancer cells than the widely used tetrahydro-4-methylene-2S-octyl-5-oxo-3R-furancarboxylic acid, and has negligible effects on the growth and proliferation of noncancerous mammary epithelial cells. Our studies have confirmed the value of using potent and selective FASN inhibitors in the treatment of BC cells and have shown that the availability of exogenous lipoproteins may impact both cancer cell FA metabolism and survival.

• Authors: Leslie E Lupien, Evan M Dunkley, Margaret J Maloy, Ian B Lehner, Maxwell G Foisey, Maddison E Ouellette, Lionel D Lewis, Darcy Bates Pooler, William B Kinlaw, Paul W Baures
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 371 Issue 1 Pg. 171-185 (10 2019) ISSN: 1521-0103 [Electronic] United States
• PMID: 31300609 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Fatty Acid Synthases
• Thiolester Hydrolases

Topics

• Antineoplastic Agents (pharmacology, toxicity)
• Catalytic Domain
• Cell Proliferation (drug effects)
• Enzyme Inhibitors (pharmacology, toxicity)
• Epithelial Cells (drug effects)
• Fatty Acid Synthases (antagonists & inhibitors, chemistry, metabolism)
• Humans
• MCF-7 Cells
• Protein Binding
• Substrate Specificity
• Thiolester Hydrolases (antagonists & inhibitors, chemistry)