Discovery of GSK837149A, an inhibitor of human fatty acid synthase targeting the β‐ketoacyl reductase reaction

Vázquez, María J.; Leavens, William J.; Liu, Ronggang; Rodríguez, Beatriz; Read, Martin; Richards, Stephen M.; Winegar, Deborah A.; Domínguez, Juan M.

doi:10.1111/j.1742-4658.2008.06314.x

Cited by 46 publications

(25 citation statements)

References 31 publications

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“…The dibenzenesulfonamide urea GSK837149A was identified as a low, nanomolar FASN inhibitor by high-throughput screening at GlaxoSmithKline. Biochemical studies showed that GSK837149A is a reversible inhibitor of the FASN β-ketoacyl reductase domain, but its poor cell permeability prevented the study of its mechanism in cells [78]. A systematic screening of 250,000 natural product extracts led to the isolation of platensimycin as a potent inhibitor of bacterial FabF/B with a broad-spectrum Gram-positive antibacterial activity [79].…”

Section: Fasn As a Potential Drug Target In Cancer Therapymentioning

confidence: 99%

“…Their study can be hampered by their lack of potency, selectivity or cell permeability [48,59,65,78]. FASN inhibition initiates selective apoptosis of cancer cells both in vivo and in vitro , which may involve accumulation of toxic intermediary metabolite malonyl-CoA with reduction of both membrane synthesis and phospholipid function leading to both cytostatic and cytotoxic effects [23,80].…”

Section: Mechanism Of Action Of Fasn Inhibitorsmentioning

confidence: 99%

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Fatty Acid Synthase As a Potential Therapeutic Target in Cancer

et al. 2010

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Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis. Overexpression of FASN is common in many cancers, and accumulating evidence suggests that it is a metabolic oncogene with an important role in tumor growth and survival, making it an attractive target for cancer therapy. Early small-molecule FASN inhibitors such as cerulenin, C75 and orlistat have been shown to induce apoptosis in several cancer cell lines and to induce tumor growth delay in several cancer xenograft models but their mechanism is still not well understood. These molecules suffer from pharmacological limitations and weight loss as a side effect that prevent their development as systemic drugs. Several potent inhibitors have recently been reported that may help to unravel and exploit the full potential of FASN as a target for cancer therapy in the near future. Furthermore, novel sources of FASN inhibitors, such as green tea and dietary soy, make both dietary manipulation and chemoprevention potential alternative modes of therapy in the future.

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Section: Fasn As a Potential Drug Target In Cancer Therapymentioning

confidence: 99%

Section: Mechanism Of Action Of Fasn Inhibitorsmentioning

confidence: 99%

Fatty Acid Synthase As a Potential Therapeutic Target in Cancer

et al. 2010

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“…The mammalian KR has received some attention as a potential anti-cancer target, and compounds have been identified as selective inhibitors. 144 …”

Section: -Ketoacyl Acp Reductase (Kr)mentioning

confidence: 99%

Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering

2015

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Fatty acids are primary metabolites synthesized by complex, elegant, and essential biosynthetic machinery. Fatty acid synthases resemble an iterative assembly line, with an acyl carrier protein conveying the growing fatty acid to necessary enzymatic domains for modification. Each catalytic domain is a unique enzyme spanning a wide range of folds and structures. Although they harbor the same enzymatic activities, two different types of fatty acid synthase architectures are observed in nature. During recent years, strained petroleum supplies have driven interest in engineering organisms to either produce more fatty acids or specific high value products. Such efforts require a fundamental understanding of the enzymatic activities and regulation of fatty acid synthases. Despite more than one hundred years of research, we continue to learn new lessons about fatty acid synthases’ many intricate structural and regulatory elements. In this review, we summarize each enzymatic domain and discuss efforts to engineer fatty acid synthases, providing some clues to important challenges and opportunities in the field.

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“…Ursolic acid, a pentacyclic triterpenoid acid, as well as the tea polyphenols, epigallo-catechin gallate (EGCG) and epicatechin gallate, interact with the KR domain of FASN, thereby inhibiting its activity [73, 74]. Recently, GSK837149A was also serendipitously identified as a potent and selective inhibitor of the KR domain [75]. Unfortunately, this compound and subsequent analogs exhibit poor cellular permeability.…”

Section: Using 11c-acetate Pet To Predict Response To Therapies That mentioning

confidence: 99%

The Potential of 11C-acetate PET for Monitoring the Fatty Acid Synthesis Pathway in Tumors

DeFord-Watts¹,

Mintz²,

Kridel³

2013

CPB

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Positron emission tomography (PET) is a molecular imaging modality that provides the opportunity to rapidly and non-invasively visualize tumors derived from multiple organs. In order to do so, PET utilizes radiotracers, such as 18F-FDG and 11C-acetate, whose uptake coincides with altered metabolic pathways within tumors. Increased expression and activity of enzymes in the fatty acid synthesis pathway is a frequent hallmark of cancer cells. As a result, this pathway has become a prime target for therapeutic intervention. Although multiple drugs have been developed that both directly and indirectly interfere with fatty acid synthesis, an optimal means to assess their efficacy is lacking. Given that 11C-acetate is directly linked to the fatty acid synthesis pathway, this probe provides a unique opportunity to monitor lipogenic tumors by PET. Herein, we review the relevance of the fatty acid synthesis pathway in cancer. Furthermore, we address the potential utility of 11C-acetate PET in imaging tumors, especially those that are not FDG-avid. Last, we discuss several therapeutic interventions that could benefit from 11C-acetate PET to monitor therapeutic response in patients with certain types of cancers.

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Discovery of GSK837149A, an inhibitor of human fatty acid synthase targeting the β‐ketoacyl reductase reaction

Cited by 46 publications

References 31 publications

Fatty Acid Synthase As a Potential Therapeutic Target in Cancer

Fatty Acid Synthase As a Potential Therapeutic Target in Cancer

Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering

The Potential of 11C-acetate PET for Monitoring the Fatty Acid Synthesis Pathway in Tumors

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