Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C411Abbreviations: LDH, lactate dehydrogenase; and LDH-A4, -B4, and -C4, human lactate dehydrogenases A4, B4, and C4.

Yu, Yue; Deck, Jason A.; Hunsaker, Lucy A.; Deck, Lorraine M.; Royer, Robert E.; Goldberg, Erwin; Jagt, David L. Vander

doi:10.1016/s0006-2952(01)00636-0

Cited by 120 publications

(57 citation statements)

References 41 publications

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“…Polyphenolic naphthalene FX-11 was originally reported as a potent and selective inhibitor of LDHA [14], but this activity was later corrected [8] and in our hands was modest at best (LDHA IC 50 = 50 to 100. Several other selective LDHA inhibitors have been reported, but all have potency in the micromolar range [15-18].…”

Section: Introductionmentioning

confidence: 79%

Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells

et al. 2013

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BackgroundMost normal cells in the presence of oxygen utilize glucose for mitochondrial oxidative phosphorylation. In contrast, many cancer cells rapidly convert glucose to lactate in the cytosol, a process termed aerobic glycolysis. This glycolytic phenotype is enabled by lactate dehydrogenase (LDH), which catalyzes the inter-conversion of pyruvate and lactate. The purpose of this study was to identify and characterize potent and selective inhibitors of LDHA.MethodsHigh throughput screening and lead optimization were used to generate inhibitors of LDHA enzymatic activity. Effects of these inhibitors on metabolism were evaluated using cell-based lactate production, oxygen consumption, and 13C NMR spectroscopy assays. Changes in comprehensive metabolic profile, cell proliferation, and apoptosis were assessed upon compound treatment.Results3-((3-carbamoyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl) amino) benzoic acid was identified as an NADH-competitive LDHA inhibitor. Lead optimization yielded molecules with LDHA inhibitory potencies as low as 2 nM and 10 to 80-fold selectivity over LDHB. Molecules in this family rapidly and profoundly inhibited lactate production rates in multiple cancer cell lines including hepatocellular and breast carcinomas. Consistent with selective inhibition of LDHA, the most sensitive breast cancer cell lines to lactate inhibition in hypoxic conditions were cells with low expression of LDHB. Our inhibitors increased rates of oxygen consumption in hepatocellular carcinoma cells at doses up to 3 microM, while higher concentrations directly inhibited mitochondrial function. Analysis of more than 500 metabolites upon LDHA inhibition in Snu398 cells revealed that intracellular concentrations of glycolysis and citric acid cycle intermediates were increased, consistent with enhanced Krebs cycle activity and blockage of cytosolic glycolysis. Treatment with these compounds also potentiated PKM2 activity and promoted apoptosis in Snu398 cells.ConclusionsRapid chemical inhibition of LDHA by these quinoline 3-sulfonamids led to profound metabolic alterations and impaired cell survival in carcinoma cells making it a compelling strategy for treating solid tumors that rely on aerobic glycolysis for survival.

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Section: Introductionmentioning

confidence: 79%

Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells

et al. 2013

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“…One such compound, 7-p-trifluoromethylbenzyl-8-deoxyhemigossylic acid, has a reported K i of 13, 81, and 4 M, respectively, for human heart, muscle, and sperm LDH (12) and 0.2 M for pfLDH (4). Vander Jagt and co-workers have also investigated various N-substituted hydroxamic acid derivatives and reported 35-80 M activity versus pfLDH (13) and 0.3-10 mM activity versus human LDH (12). Modifications do not appear to affect potency significantly or the selectivity of these compounds, which appear to be competitive for pyruvate.…”

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confidence: 99%

Identification and Activity of a Series of Azole-based Compounds with Lactate Dehydrogenase-directed Anti-malarial Activity

Cameron

Read

Tranter

et al. 2004

Journal of Biological Chemistry

135

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Plasmodium falciparum, the causative agent of malaria, relies extensively on glycolysis coupled with homolactic fermentation during its blood-borne stages for energy production. Selective inhibitors of the parasite lactate dehydrogenase (LDH), central to NAD ؉ regeneration, therefore potentially provide a route to new antimalarial drugs directed against a novel molecular target. A series of heterocyclic, azole-based compounds are described that preferentially inhibit P. falciparum LDH at sub-micromolar concentrations, typically at concentrations about 100-fold lower than required for human lactate dehydrogenase inhibition. Crystal structures show these competitive inhibitors form a network of interactions with amino acids within the active site of the enzyme, stacking alongside the nicotinamide ring of the NAD ؉ cofactor. These compounds display modest activity against parasitized erythrocytes, including parasite strains with known resistance to existing anti-malarials and against Plasmodium berghei in BALB/c mice. Initial toxicity data suggest the azole derivatives have generally low cytotoxicity, and preliminary pharmocokinetic data show favorable bioavailability and circulation times. These encouraging results suggest that further enhancement of these structures may yield candidates suitable for consideration as new therapeutics for the treatment of malaria. In combination these studies also provide strong support for the validity of targeting the Plasmodium glycolytic pathway and, in particular, LDH in the search for novel anti-malarials.Plasmodium parasites are believed to lack a functional Krebs (citric acid) cycle for at least part of their life cycle and hence rely extensively on ATP generation via the anaerobic fermentation of glucose (see Ref. 1 for review). The energy requirement of the parasitized erythrocyte is such that utilization of glucose is up to 100 times greater than in nonparasitized erythrocytes (2, 3), and virtually all glucose can be accounted for by production of lactate (2). Lactate dehydrogenase (LDH), 1 the last enzyme in the glycolytic pathway in Plasmodium falciparum, is a 2-hydroxy acid oxidoreductase that converts pyruvate to lactate and simultaneously the conversion of NADH to NAD ϩ . As a constant supply of NADH is a prerequisite for glycolysis, and LDH acts as the primary source in Plasmodium for the regeneration of NADH from NAD ϩ , inhibition of LDH is expected to stop production of ATP, with subsequent P. falciparum cell death. Any compound that blocks the LDH enzyme is a potentially potent antimalarial with a different mode of action to existing drugs. As such, P. falciparum lactate dehydrogenase (pfLDH) has been suggested as a drug target by several authors (4 -6). One well recognized difficulty is that the drug must potently inhibit pfLDH yet show much less activity against the three human LDH (hsLDH) isoforms.A comparison of the crystal structures of both P. falciparum and human LDH (7,8) shows the following two key differences: namely positioning of the NADH factor, re...

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“…PfLDH possesses certain unique residues and shows some differences in enzyme kinetics when compared to the human LDH isoforms (hLDH) suggesting that PfLDH can be selectively targeted for developing antimalarial therapy. Efforts targeting PfLDH for the development of antimalarial drugs have uncovered several inhibitors including gossypol derivatives [165][166][167][168][169], azole-based compounds [170], and oxamate derivatives [171][172][173]. Oxamic acid is a competitive inhibitor of pyruvate binding in LDH.…”

Section: Glycolysismentioning

confidence: 99%

The Fight Against Drug-Resistant Malaria: Novel Plasmodial Targets and Antimalarial Drugs

Avery

Choi

Mukherjee³

2008

CMC

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Malaria, one of the major reemerging parasitic diseases, is caused by protozoal parasites belonging to the genus plasmodia. Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The current line of therapy against malaria is faced with the hurdles of a low or total lack of efficacy due to the evolution of drug-resistant strains of the malarial parasites. Preventive vaccination against malaria is an ideal solution to this problem but is not expected to arrive for at least a decade. Development of antimalarial drugs involving novel mechanisms of action is therefore of imminent importance. Several novel drug candidates of synthetic and natural products origin as well as their combination therapies are currently being evaluated for their efficacy against the drug-resistant strains of the parasites. Various plasmodial targets/pathways, such as the Purine salvage pathway, Pyrimidine biosynthesis pathway as well as the processes in the apicoplast, have been identified and are being utilized for the discovery and development of novel antimalarial therapies. This review provides an overview of the latest developments in terms of drugs, combination therapies and novel plasmodial targets being carried out to counter the menace of drug-resistant malaria.

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Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C411Abbreviations: LDH, lactate dehydrogenase; and LDH-A4, -B4, and -C4, human lactate dehydrogenases A4, B4, and C4.

Cited by 120 publications

References 41 publications

Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells

Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells

Identification and Activity of a Series of Azole-based Compounds with Lactate Dehydrogenase-directed Anti-malarial Activity

The Fight Against Drug-Resistant Malaria: Novel Plasmodial Targets and Antimalarial Drugs

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