Discovery of human lactate dehydrogenase A (LDHA) inhibitors as anticancer agents to inhibit the proliferation of MG-63 osteosarcoma cells

Fang, Aiping; Zhang, Qi; Fan, Huimin; Zhou, Yaying; Yao, Yuqin; Zhang, Yue; Huang, Xiao‐Jun

doi:10.1039/c7md00222j

Cited by 27 publications

(17 citation statements)

References 26 publications

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“…Given the importance of lactate metabolism in different types of cancers, the discovery and development of new molecules that could inhibit LDHA activity is urgently needed. Only a few molecules have started tests in clinical trials, for this reason there is a trend to optimize existing compounds, such is the case of compound 5, that was used as a template for molecular docking, then the 200 top-ranked compounds with the highest total binding scores were selected, however, only 1 molecule (compound 11: 11c) from 7 candidates was employed for further biological validation (180). 11c maintains the same hydrogen bond interactions as compound 5 in the binding model and exhibits extra hydrogen bond interactions with the residues Asp 194 and Thr 247 in LDHA, which could give rise to its inhibitory activity against LDHA.…”

Section: Therapeutic Approaches In Lactate Metabolismmentioning

confidence: 99%

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

et al. 2019

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Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose producing large volumes of lactate even in the presence of oxygen, this process is known as "Warburg effect or aerobic glycolysis." As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.

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Section: Therapeutic Approaches In Lactate Metabolismmentioning

confidence: 99%

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

et al. 2019

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“…One of the compounds identified ( C ) showed very good LDHA inhibition potency in vitro with an IC 50 value of 0.33 μM. 12 …”

Section: Introductionmentioning

confidence: 97%

Symmetric molecules with 1,4-triazole moieties as potent inhibitors of tumour-associated lactate dehydrogenase-A

Altamimi

Alafeefy

Balode

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of symmetric molecules incorporating aryl or pyridyl moieties as central core and 1,4-substituted triazoles as a side bridge was synthesised. The new compounds were investigated as lactate dehydro-genase (LDH, EC 1.1.1.27) inhibitors. The cancer associated LDHA isoform was inhibited with IC50 = 117–174 µM. Seven compounds exhibited better LDHA inhibition (IC50 117–136 µM) compared to known LDH inhibitor – galloflavin (IC50 157 µM).

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“…Due to the known role of hLDHA in the “Warburg effect” in malignant cells [ 130 ], the inhibition of this enzyme has been considered as a strategy for diminishing the energy supply in cancer cells, reducing in that sense, the invasive potential of different kinds of cancer, such as breast carcinoma [ 131 , 132 , 133 , 134 , 135 ], pancreatic cancer [ 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 ], brain tumor [ 146 ], hepatocellular carcinoma [ 131 , 134 , 147 ], osteosarcoma [ 148 , 149 , 150 , 151 ], lung carcinoma [ 134 , 152 , 153 , 154 ], ovarian cancer [ 138 ], bladder cancer [ 155 ], colorectal cancer [ 134 , 138 , 155 ], mesothelioma [ 138 ], melanoma [ 134 ], leukemia [ 134 ], lymphoma [ 136 ], gastric cancer [ 156 ], Ewing’s sarcoma [ 145 ], leiomyomatosis, and renal cancer [ 157 ], achieving the in vitro , and in some cases in vivo , reduction of cancer cells.…”

Section: Enzyme Inhibitors For the Treatment Of Phsmentioning

confidence: 99%

Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

Moya-Garzón

Gómez-Vidal

Alejo-Armijo

et al. 2021

JPM

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Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

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Discovery of human lactate dehydrogenase A (LDHA) inhibitors as anticancer agents to inhibit the proliferation of MG-63 osteosarcoma cells

Cited by 27 publications

References 26 publications

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

Symmetric molecules with 1,4-triazole moieties as potent inhibitors of tumour-associated lactate dehydrogenase-A

Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

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