Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors

Qian, Yimin; Ahmad, Mushtaq; Chen, Shaoqing; Gillespie, Paul; Le, Nam T.; Mennona, Frank; Mischke, Steven; So, Sung‐Sau; Wang, Hong; Burghardt, Charles; Tannu, Shahid; Conde-Knape, Karin; Kochan, Jarema; Bolin, David

doi:10.1016/j.bmcl.2011.09.009

Cited by 25 publications

(21 citation statements)

References 12 publications

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“…However, we did not observe increased XBP1s levels and activity with lower toxicity. 53,54 It is important to identify potential biomarkers, which may include the expression of GFAT, for patient selection for combination therapy with GFAT-targeting regimens.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Chen

Kieu

Saxton

et al. 2019

Molecular Carcinogenesis

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Platinum anticancer agents are essential components in chemotherapeutic regimens for non–small‐cell lung cancer (NSCLC) patients ineligible for targeted therapy. However, platinum‐based regimens have reached a plateau of therapeutic efficacy; therefore, it is critical to implement novel approaches for improvement. The hexosamine biosynthesis pathway (HBP), which produces amino‐sugar N‐acetyl‐glucosamine for protein glycosylation, is important for protein function and cell survival. Here we show a beneficial effect by the combination of cisplatin with HBP inhibition. Expression of glutamine:fructose‐6‐phosphate amidotransferase (GFAT), the rate‐limiting enzyme of HBP, was increased in NSCLC cell lines and tissues. Pharmacological inhibition of GFAT activity or knockdown of GFATimpaired cell proliferation and exerted synergistic or additive cytotoxicity to the cells treated with cisplatin. Mechanistically, GFAT positively regulated the expression of binding immunoglobulin protein (BiP; also known as glucose‐regulated protein 78, GRP78), an endoplasmic reticulum chaperone involved in unfolded protein response (UPR). Suppressing GFAT activity resulted in downregulation of BiP that activated inositol‐requiring enzyme 1α, a sensor protein of UPR, and exacerbated cisplatin‐induced cell apoptosis. These data identify GFAT‐mediated HBP as a target for improving platinum‐based chemotherapy for NSCLC.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Chen

Kieu

Saxton

et al. 2019

Molecular Carcinogenesis

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“…As a glutamine analog, DON is not specific to GFAT, but it has gone through numerous clinical trials in the past, therefore its toxicity is known and efforts to minimize the side effects are ongoing (28,29). New inhibitors for GFAT are also in development (30)(31)(32). Another advantage of targeting GFAT/HBP is that inhibition of the pathway itself has anti-cancer properties, as we (13)and others have demonstrated (33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein and improves immune response

Chen

Saxton

2020

Preprint

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Immunotherapy using checkpoint blockers (antibodies) has been a major advance in recent years in the management of various types of solid cancers including lung cancer. One target of checkpoint blockers is programmed death ligand 1 (PD-L1) expressed by cancer cells, which engages programmed death 1 (PD-1) on T cells and Natural Killer (NK) cells resulting in suppression of their activation and cancer-killing function, respectively. Apart from antibodies, other clinically relevant agents that can inhibit PD-L1 are limited. PD-L1 protein stability depends on its glycosylation. Here we show that L-glutamine:D-fructose amidotransferase 1 (GFAT1) a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP) which produces uridine diphosphate-N-acetyl-β-glucosamine (UDP-GlcNAc), a precursor for glycosylation, is required for the stability of PD-L1 protein. Inhibition of GFAT1 activity markedly reduced interferon γ (IFNγ)-induced PD-L1 levels in various lung cancer cell lines. GFAT1 inhibition suppressed glycosylation of PD-L1 and accelerated its proteasomal degradation. Importantly, inhibition of GFAT1 in IFNγ-treated cancer cells enhanced the activation of T cells and the cancer-killing activity of NK cells. These findings support using GFAT1 inhibitors to manipulate PD-L1 protein level that could augment the efficacy of immunotherapy for lung cancer.

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“…The activity of several Glx consuming or producing enzymes ( e.g. γ -glutamyltransferase [35-42], glutamine fructose-6-phosphate amidotransferase [43], glutamate pyruvate transaminase [40]) were reported to be associated with diabetes mellitus, impaired glucose tolerance and insulin resistance and are used as biomarkers to monitor liver functionality. Glutamate links the tricarboxylic acid (TCA) cycle with amino acid biosynthesis and degradation.…”

Section: Discussionmentioning

confidence: 99%

A distinct metabolic signature predicts development of fasting plasma glucose

Hische

Larhlimi

Schwärz

et al. 2012

J Clin Bioinformatics

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BackgroundHigh blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods.MethodsWe took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort.ResultsWe found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis.ConclusionsWe demonstrate that metabolites identified using a high-throughput method (GC-MS) perform well in predicting the development of fasting plasma glucose over several years. Notably, not single, but a complex pattern of metabolites propels the prediction and therefore reflects the complexity of the underlying molecular mechanisms. This result could only be captured by application of multivariate statistical approaches. Therefore, we highly recommend the usage of statistical methods that seize the complexity of the information given by high-throughput methods.

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Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors

Cited by 25 publications

References 12 publications

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non–small‐cell lung cancer cells

Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein and improves immune response

A distinct metabolic signature predicts development of fasting plasma glucose

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