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. s This article has supplemental material available at jpet.aspetjournals.org.

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

“…In breast cancer, ADP and FASN have been reported to be associated with the immune-biomarker classification, which is a surrogate for molecular subtyping reflecting the different metabolic pathways [ 9 , 22 ]. Given that FASN inhibitors have shown cytotoxicity in various cancers [ 18 , 38 ], the different expressions of ADP and FASN in accordance with the SDC subtypes assessed by the AR (instead of ER or PR for breast cancer), HER2, and Ki-67 status might imply that inhibiting proteins related to lipid metabolism is a possible therapeutic approach for some subtypes. Although we failed to prove the influence of the FASN expression in SDC on the prognosis, patients with a high FASN expression score may be suitable for FASN inhibitor therapy in the future, regardless of the prognostic significance.…”

The chemical composition of the ethanolic extract from Chromolaena odorata leaves correlates with the cytotoxicity exhibited against colorectal and breast cancer cell lines

“…It means that these protease inhibitors can prevent secondary infection from breast and colorectal cancer. Besides, enzyme inhibitors that are owned by several C. odorata compounds can bind cancer cell metabolic enzymes to reduce nutrient intake and inhibit the formation of enzyme-substrate complexes' and prevent catalytic reactions so that they can kill pathogens and improve metabolic imbalances (Lupien et al, 2019). It assumed that C. odorata could balance average cell growth and decrease (apoptosis) against cancer cells (Robin et al, 2018).…”

Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis

“…68 Upregulation of FASN occurs in most human cancers, including HCC. [69][70][71][72][73] Therefore, FASN provides a potential oncologic target and diagnostic marker for NAFLD formation. [68][69][70][72][73][74][75] PGE2/PTGES2 is induced in human and rodent NASH livers, [76][77][78] and is upregulated in several types of cancer, including colorectal cancer, 79,80 breast cancer, 81,82 and HCC.…”

“…[69][70][71][72][73] Therefore, FASN provides a potential oncologic target and diagnostic marker for NAFLD formation. [68][69][70][72][73][74][75] PGE2/PTGES2 is induced in human and rodent NASH livers, [76][77][78] and is upregulated in several types of cancer, including colorectal cancer, 79,80 breast cancer, 81,82 and HCC. 83,84 Deregulated genes involved in "insulin resistance" or "regulation of inflammatory response" included solute carrier family 2 member 4 (Slc2a4), interleukin 17 (Il17), and interleukin 17 receptor A (Il17ra).…”