Publications by authors named "Susan M Medghalchi"
Article Synopsis
- There is a growing need for effective anti-obesity drugs, but current options are limited; researchers are focusing on inhibiting an enzyme called GPAT to help with weight loss.
- Recent studies have shown that certain compounds, specifically 2-(alkanesulfonamido)benzoic acids, can moderate GPAT activity and lead to promising weight loss results.
- A newly synthesized compound, 4-([1,1'-biphenyl]-4-carbonyl)-2-(octanesulfonamido)benzoic acid, emerged as the strongest GPAT inhibitor, with an IC value of 8.5 µM, while modifications like adding hydroxyl or fluoro groups decreased its effectiveness.
Storage of excess calories as triglycerides is central to obesity and its associated disorders. Glycerol-3-phosphate acyltransferases (GPATs) catalyze the initial step in acylglyceride syntheses, including triglyceride synthesis. We utilized a novel small-molecule GPAT inhibitor, FSG67, to investigate metabolic consequences of systemic pharmacological GPAT inhibition in lean and diet-induced obese (DIO) mice.
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- Glycerol 3-phosphate acyltransferase (GPAT) isozymes are crucial for fat synthesis in mammals, making them targets for obesity treatments.
- The study developed and tested various cyclic bisubstrate and transition state analogs as potential GPAT inhibitors but found them less effective than a previous benzoic acid series.
- In silico docking experiments revealed that the designed compounds might be blocked by two protein loops in the enzyme’s active site, suggesting that future inhibitors should utilize planar structures to improve binding and effectiveness.
Article Synopsis
- Obesity and diseases related to high triacylglycerol levels are rising, especially in the U.S.
- Glycerol 3-phosphate acyltransferase (GPAT) is a key enzyme involved in glycerolipid production, specifically in acylating glycerol 3-phosphate.
- Researchers developed and tested a range of benzoic and phosphonic acid compounds, finding that 2-(nonylsulfonamido)benzoic acid (15g) has moderate inhibitory effects on GPAT in mitochondrial assays.
Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight.
Am J Physiol Regul Integr Comp Physiol
February 2008
Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified.
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- Fatty acid synthase (FAS) is overexpressed in many cancers, making it a potential target for therapy, but previous inhibitors caused severe anorexia in test animals due to fatty acid oxidation stimulation.
- C93, a newly designed inhibitor, was tested and shown to effectively inhibit FAS activity without affecting fatty acid oxidation in lung cancer cells.
- The use of C93 resulted in significant tumor growth inhibition in preclinical lung cancer models without causing anorexia or weight loss, suggesting it could be a promising treatment option for non-small cell lung cancer.
Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity.
View Article and Find Full Text PDFFatty acid synthase (FAS) catalyzes the synthesis of palmitate from the sequential condensation of an acetyl primer with two carbon units added from malonyl-CoA. Inhibition of the beta-ketoacyl synthase domain of mammalian FAS leads to selective cytotoxicity to various cancer cell lines in vitro and in vivo. Also, inhibitors of FAS can cause reduced food intake and body weight in mice.
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- - C75, a fatty acid synthase inhibitor, induces apoptosis in human cancer cells by increasing malonyl-CoA levels, but recent studies show it stimulates fatty acid oxidation in MCF-7 breast cancer cells despite this increase.
- - Key findings reveal that C75 inhibits fatty acid synthesis, promotes lipid oxidation, and accelerates the decay of membrane lipids, while a reduced form, C273, shows no toxic effects.
- - C75 triggers apoptosis specifically during the S phase of the cell cycle by interfering with phospholipid synthesis, while the compound TOFA, although inhibiting fatty acid synthesis, does not induce apoptosis and can block the effects of C75 when applied beforehand.