New Synthetic Inhibitors of Fatty Acid Synthase with Anticancer Activity (original) (raw)
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Novel anti-fatty acid synthase compounds with anti-cancer activity in HER2+ breast cancer
Annals of the New York Academy of Sciences, 2010
Fatty acid synthase (FASN) expression and activity has emerged as a common phenotype in most human carcinomas, including breast cancer, and its expression is tightly linked to HER2 signaling pathways. The development of inhibitors of FASN activity has consequently appeared as a novel antitarget modality for treating cancer. However, the clinical use of FASN inhibitors, such as cerulenin, C75, and epigallocatechin 3-gallate (EGCG), is limited by anorexia and induced body weight loss or by its low in vivo potency and stability. Here, we summarize the design and development of G28UCM, the lead-compound of a novel family of synthetic FASN inhibitors, with both in vitro and in vivo activity in a human breast cancer model of FASN + and HER2 + .
A new class of human fatty acid synthase inhibitors: Synthesis and their anticancer evaluation
2018
thiadiazoles have been designed, synthesized and screened for their in vitro antitumour activity against breast cancer cell lines. Three compounds namely, 3pentadecyl-6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (6e), 3-heptadecyl-6-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (6j) and 3-heptadecyl-6(3-nitrophenyl)[1,2,4]triazolo[3,4b][1,3,4]-thiadiazole (6g) have displayed comparable activities towards human breast cancer lines. Molecular docking studies have been carried out on the crystal structure of human fatty acid synthase thioesterase domain (2PX6) by using GLIDE integrated Maestro 9.3 version. The designed compounds have shown good binding interactions with the active site residues present in the enzyme and have given very good G-scores when compared to the known inhibitor orlistat.
(-)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects
European journal of medicinal chemistry, 2017
C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (-)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2- and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial ...
Lipids in Health and Disease, 2013
Background: Preparation of some novel heterocyclic compounds with long alkyl and alkenyl chain of cytotoxic activity. Methods: Gamma linolenic acid, a poly unsaturated fatty acid and stearic acid, a saturated fatty acid were isolated from the microalga Spirulina platensis. Some novel gamma linolenic acid and stearic acid analogues having 1,3, 4-oxadiazole and 1,2,4-triazole were synthesized and characterized by IR, 1 H NMR, 13 C NMR and mass spectral analysis. Cytotoxicity of these compounds was evaluated by the growth inhibition of A-549 cells in-vitro. Results: Compound 1 and 3 showed comparable cytotoxicity against the human lung carcinoma A-549 cell lines.
Anticancer Research, 2020
Aberrant fatty acid (FA) metabolism has long been recognized in colorectal cancer (CRC) cells. Since de novo lipogenesis is required for CRC tumour growth and survival, the inhibition of FA metabolism is a promising potential therapeutic target. Inhibition of the opposite process, β-oxidation of FAs, has also showed promising results in many CRC models. For patients with CRC, both FA synthesis and β-oxidation inhibitors are promising potential therapeutic options as monotherapies or as combination therapies with other anticancer agents. In this review, we discuss recent reports concerning inhibitors of FA synthesis and β-oxidation in various CRC models. The exact mechanisms of action of the selected compounds described in this review remain unknown and require precise evaluation before the development of new successful therapies for CRC is possible. Colorectal cancer (CRC) is among the most common types of cancer, accounting for approximately 10% of cancer incidence and mortality in both sexes (1, 2). Early detection owing to advanced screening methods (3, 4) has led to a reduction in death rates over the past several decades (5). However, some modifiable risk factors, such as poor diet and inactive lifestyle, are projected to contribute to increased incidence rates globally (5), especially affecting people in developing nations and underprivileged social classes (6, 7). Advances in understanding the pathophysiological alterations underlying this disease have led to a wide array of treatment options being available for the management of CRC. In addition to endoscopic and surgical excision, radiotherapy, and chemotherapy, drugs are used for the treatment of CRC and include biologicals and immunotherapeutics (7). Recently, for the development of successful therapeutic strategies in the treatment of cancer, lipid metabolism has been considered an avenue worthy of pursuit (8, 9). Metabolic reprogramming of cancer cells facilitates enhanced proliferation and, in later stages cell dissemination, processes in which alterations of lipid metabolism play pivotal roles. Lipids serve as structural components of membranes, fuel sources for rapidly growing and dividing cells, and secondary messengers (9, 10). In particular, researchers focus on fatty acid (FA) metabolism because FAs are the main building blocks for other, more complex classes of lipids, such as phospholipids, sphingolipids, glycosphingolipids or triglycerides, and therefore contribute to the regulation of many different biochemical processes. Aberrant FA metabolism has long been recognized in CRC cells (11), thus providing potential targets for therapeutics. A considerable body of work shows that de novo lipogenesis is required for CRC tumour growth and survival (12-15). FA synthase (FASN) provides palmitate for cancer cells for intensive membrane formation, enhancing cell resistance to oxidative damage and to chemotherapeutics due to increased lipid saturation (16), provides fuel for FA oxidation, and promotes the metastatic capacity of CRC (12, 17, 18). The palmitate from FASN-driven lipogenesis can also be modified via elongases (ELOVLs) or desaturated by stearoyl-CoA desaturase (SCD1), and these modifications may be targets of new therapy design (9). Indeed, CRC exhibits both the enhanced elongation of FAs (19, 20) and up-regulation of SCD1 activity (21, 22). Upon activation by an enzyme from the long-chain acyl-CoA synthetase family (ACSL), endogenously synthesized or exogenous FAs can be incorporated into triglycerides and cholesterol esters, which 4843
Oncotarget, 2018
Fatty Acid Synthase (FASN), a key enzyme of lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity and and a favorable tolerability profile in a Phase I clinical trial. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition. CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatt...
Fatty Acids and Their Analogues as Anticancer Agents
Fatty Acids, 2017
Recent research supports the beneficial effects of dietary polyunsaturated fatty acids (PUFAs) on inhibiting tumour development. Long-chain fatty acids modulate the tumour cell response to chemotherapeutic drugs. Investigators recently claimed high dietary intake of omega-6 polyunsaturated fatty acids such as linoleic acid especially in association with a low intake of omega-3 polyunsaturated fatty acids such as docosahexaenoic acid to increase risks for cancers of the breast, colon and possibly prostate. In addition to these facts, a number of investigations have demonstrated that a modified fatty acid analogues are promising molecules in cancer prevention and have potential in the treatment of cancer. Although billions of dollars have been spent on research and development on anticancer drugs, the disease remains uncontrolled. It is expected that anticancer agents preferentially kill tumour cells without causing adverse effects on normal cells. But this is rarely achieved with the existing cancer therapy. Hence, polyunsaturated fatty acids have come under the category of nutraceuticals/functional foods; their exploration in the treatment of cancer may be considered as safe. This chapter describes the effects of long-chain fatty acids and their analogues in cancer chemotherapy.