Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation

Xiang, Sichuan; Huang, Ding; He, Qiaolin; Li, Jie; Tam, Kin Yip; Zhang, Shaolin; He, Yun

doi:10.1016/j.ejmech.2020.112579

Cited by 13 publications

(3 citation statements)

References 25 publications

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“…An investigation designed two PDK/LDHA inhibitors (20e and 20k) that could decrease lactate formation and enhance oxygen consumption in A549 cells. These data indicate that these inhibitors can regulate the glucose metabolic pathways in cancer cells [ 140 ].…”

Section: Dual Pathway Inhibitorsmentioning

confidence: 99%

Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors

Chen

Lan

Yao

et al. 2023

Cancers

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The metabolism of tumors and immune cells in the tumor microenvironment (TME) can affect the fate of cancer and immune responses. Metabolic reprogramming can occur following the activation of metabolic-related signaling pathways, such as phosphoinositide 3-kinases (PI3Ks) and the mammalian target of rapamycin (mTOR). Moreover, various tumor-derived immunosuppressive metabolites following metabolic reprogramming also affect antitumor immune responses. Evidence shows that intervention in the metabolic pathways of tumors or immune cells can be an attractive and novel treatment option for cancer. For instance, administrating inhibitors of various signaling pathways, such as phosphoinositide 3-kinases (PI3Ks), can improve T cell-mediated antitumor immune responses. However, dual pathway inhibitors can significantly suppress tumor growth more than they inhibit each pathway separately. This review discusses the latest metabolic interventions by dual pathway inhibitors as well as the advantages and disadvantages of this therapeutic approach.

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Section: Dual Pathway Inhibitorsmentioning

confidence: 99%

Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors

Chen

Lan

Yao

et al. 2023

Cancers

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“…selected six active molecules from a database of 500,000 molecules using high-throughput virtual screening, optimized their structures, and developed a new dual-target molecule with nanomolar activity against PDK1 and LDHA. The results showed that this molecule inhibited the activity of PDK1 and LDHA, significantly reduced the production of lactate in tumor cells, increased oxygen consumption, and regulated glucose metabolism ( 103 ).…”

Section: Hif-1α Inhibits Oxphosmentioning

confidence: 99%

Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis

et al. 2022

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Renal fibrosis is the result of renal tissue damage and repair response disorders. If fibrosis is not effectively blocked, it causes loss of renal function, leading to chronic renal failure. Metabolic reprogramming, which promotes cell proliferation by regulating cellular energy metabolism, is considered a unique tumor cell marker. The transition from oxidative phosphorylation to aerobic glycolysis is a major feature of renal fibrosis. Hypoxia-inducible factor-1 α (HIF-1α), a vital transcription factor, senses oxygen status, induces adaptive changes in cell metabolism, and plays an important role in renal fibrosis and glucose metabolism. This review focuses on the regulation of proteins related to aerobic glycolysis by HIF-1α and attempts to elucidate the possible regulatory mechanism underlying the effects of HIF-1α on glucose metabolism during renal fibrosis, aiming to provide new ideas for targeted metabolic pathway intervention in renal fibrosis.

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“… However, the systematical modification of CAA and its detailed structure–activity relationship (SAR) studies are limited. Continuing our efforts in discovering novel therapeutics based on natural and designed products, − herein we report the optimization and SAR analysis of a series of novel CAA analogues and the biological validation of the analogues as dual Topo I and II inhibitors with improved pharmacological profiles.…”

Section: Introductionmentioning

confidence: 99%

Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity

et al. 2022

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Calothrixin A (CAA) is a dual Topo I and II inhibitor but exhibits poor antiproliferative activities and water solubility. Herein, a library of novel CAA analogues was synthesized. Among them, compound F16 exhibited superior water solubility (>5 mg/mL) as compared to CAA (<5 μg/mL). The mechanism of action studies confirmed that F16 acted as a dual Topo I and II poison. Furthermore, F16 displayed potent antiproliferative activities against high Topo I and II expression cell lines A375 and HCT116, with IC50 values of 20 and 50 nM, respectively. In xenograft models, F16 reduced the tumor growth at a dose of 10 or 20 mg/kg without apparent effect on the mouse weight, while the clinically used Topo II inhibitor VP-16 dramatically reduced the mouse weight. Collectively, our data demonstrated that F16 could be a promising lead for the development of novel dual Topo I and II antitumor agents.

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Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation

Cited by 13 publications

References 25 publications

Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors

Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors

Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis

Optimization of the Natural Product Calothrixin A to Discover Novel Dual Topoisomerase I and II Inhibitors with Improved Anticancer Activity

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