Discovery of potent 4-aminoquinoline hydrazone inhibitors of NRH:quinoneoxidoreductase-2 (NQO2)

Hussein, Buthaina; Ikhmais, Balqis; Kadirvel, Manikandan; Magwaza, Rachael N.; Halbert, Gavin; Bryce, Richard A.; Stratford, Ian J.; Freeman, Sally

doi:10.1016/j.ejmech.2019.111649

Cited by 12 publications

(12 citation statements)

References 34 publications

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“…NQO2 is a flavoprotein that catalyzes the two-electron reduction of various quinones, redox dyes, and the vitamin K menadione. It has been frequently identified as a promising therapeutic target in addition to NQO1 [NAD(P)H: quinone oxidoreductase 1] in cancers due to its vital roles played in cancer initiation and progression, possibly via regulating the generation of ROS ( Hussein et al, 2019 ; Zhang et al, 2020 ; Schepers et al, 2021 ). NQO2 might serve as a valuable target for erianin and be worth future investigation.…”

Section: Resultsmentioning

confidence: 99%

Anticancer Activity of Erianin: Cancer-Specific Target Prediction Based on Network Pharmacology

Yan

Zhang

Liu

et al. 2022

Front. Mol. Biosci.

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Erianin is a major bisbenzyl compound extracted from Dendrobium chrysotoxum Lindl., an important traditional Chinese herb. In recent years, a growing body of evidence has proved the potential therapeutic effects of erianin on various cancers, including hepatoma, melanoma, non-small-cell lung carcinoma, myelogenous leukemia, breast cancer, and osteosarcoma. Especially, the pharmacological activities of erianin, such as antioxidant and anticancer activity, have been frequently demonstrated by plenty of studies. In this study, we firstly conducted a systematic review on reported anticancer activity of erianin. All updated valuable information regarding the underlying action mechanisms of erianin in specific cancer was recorded and summarized in this paper. Most importantly, based on the molecular structure of erianin, its potential molecular targets were analyzed and predicted by means of the SwissTargetPrediction online server (http://www.swisstargetprediction.ch). In the meantime, the potential therapeutic targets of 10 types of cancers in which erianin has been proved to have anticancer effects were also predicted via the Online Mendelian Inheritance in Man (OMIM) database (http://www.ncbi.nlm.nih.gov/omim). The overlapping targets may serve as valuable target candidates through which erianin exerts its anticancer activity. The clinical value of those targets was subsequently evaluated by analyzing their prognostic role in specific cancer using Kaplan-Meier plotter (http://Kmplot.com/analysis/) and Gene Expression Profiling Interactive Analysis (GEPIA) (http://gepia.cancer-pku.cn/). To better assess and verify the binding ability of erianin with its potential targets, molecular flexible docking was performed using Discovery Studio (DS). The valuable targets obtained from the above analysis and verification were further mapped to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway using the Database for Annotation, Visualization and Integrated Discovery (DAVID) (http://david.abcc.ncifcrf.gov/) to explore the possible signaling pathways disturbed/regulated by erianin. Furthermore, the in silico prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of erianin was also performed and provided in this paper. Overall, in this study, we aimed at 1) collecting all experiment-based important information regarding the anticancer effect and pharmacological mechanism of erianin, 2) providing the predicted therapeutic targets and signaling pathways that erianin might act on in cancers, and 3) especially providing in silico ADMET properties of erianin.

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Section: Resultsmentioning

confidence: 99%

Anticancer Activity of Erianin: Cancer-Specific Target Prediction Based on Network Pharmacology

Yan

Zhang

Liu

et al. 2022

Front. Mol. Biosci.

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“…NQO2 was reported to participate in numerous human diseases, including cancer [ 32 ] and neurodegenerative diseases. [ 33 ] Previous study showed that loss of NQO2 displayed slower proliferation and G1 phase cell accumulation in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Curcumol Overcomes TRAIL Resistance of Non‐Small Cell Lung Cancer by Targeting NRH:Quinone Oxidoreductase 2 (NQO2)

Zhang

Zhou

et al. 2020

Advanced Science

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Resistance to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) of cancer cell remains a key obstacle for clinical cancer therapies. To overcome TRAIL resistance, this study identifies curcumol as a novel safe sensitizer from a food-source compound library, which exhibits synergistic lethal effects in combination with TRAIL on non-small cell lung cancer (NSCLC). SILAC-based cellular thermal shift profiling identifies NRH:quinone oxidoreductase 2 (NQO2) as the key target of curcumol. Mechanistically, curcumol directly targets NQO2 to cause reactive oxygen species (ROS) generation, which triggers endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) death receptor (DR5) signaling, sensitizing NSCLC cell to TRAIL-induced apoptosis. Molecular docking analysis and surface plasmon resonance assay demonstrate that Phe178 in NQO2 is a critical site for curcumol binding. Mutation of Phe178 completely abolishes the function of NQO2 and augments the TRAIL sensitization. This study characterizes the functional role of NQO2 in TRAIL resistance and the sensitizing function of curcumol by directly targeting NQO2, highlighting the potential of using curcumol as an NQO2 inhibitor for clinical treatment of TRAIL-resistant cancers.

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“…Some reference inhibitors of NQO2. Compound A: Imidazoacridin-6-one 6a1 (Dunstan et al, 2011); Compound B: Furan-amidine 1 (Alnabulsi et al, 2018); Compound C: DB75 (Purfield et al, 2008); Compound D: Afobazole (Kadnikov et al, 2014); Compound E: Triazoloacridin-6-one 7c (Nolan et al, 2010b); Compound F: S28128 (Mailliet et al, 2005); Compound G: Resveratrol analog 1v (St. John et al, 2013); Compound H: Resveratrol (Buryanovskyy et al, 2004); Compound I: Dabigatran ethyl ester (Michaelis et al, 2012); Compound J: 1-Hydroxyphenazine 16 (Conda-Sheridan et al, 2010); Compound K: Indolone 12 (Volkova et al, 2012); Compound L: MCA-NAT (Pegan et al, 2011); Compound M: Melatonin (Calamini et al, 2008); Compound N: Xanthohumol D (Choi et al, 2011); Compound O: Indolequinone 2g (Dufour et al, 2011); Compound P: Chrysoeriol (Boutin et al, 2005); Compound Q: Benzo(a)pyrene (Zhao et al, 1997); Compound R: Ammosamide analog 38 (Reddy et al, 2012); Compound S: S29434 ; Compound T: Casimiroin analog 1j (Maiti et al, 2009); Compound U: 4-Aminoquinoline hydrazone 7d (Hussein et al, 2019). details), leading to a possible major breakthrough in NQO2 molecular pharmacology.…”

Section: Biochemistrymentioning

confidence: 99%

“…John et al, 2013), dunnione (Chhour et al, 2019), curcumin (Meiyanto et al, 2019), casimiroin (Maiti et al, 2009), and ammosamide B (Reddy et al, 2012). The main series of structures leading to potent inhibitors can be reduced to six chemical families, as exemplified in Figure 3: quinolines (Kwiek et al, 2004), imidazoacridin-6-ones (Nolan et al, 2010c;Dunstan et al, 2011), benzimidazole derivatives (Kadnikov et al, 2014(Kadnikov et al, , 2015, furan-amidines (Alnabulsi et al, 2016(Alnabulsi et al, , 2018, 4-aminoquinoline hydrazine (Hussein et al, 2019), and our indoyl-indol series (Boussard et al, 2006), as discussed thoroughly in the following section.…”

Section: Inhibitorsmentioning

confidence: 99%

Molecular Pharmacology of NRH:Quinone Oxidoreductase 2: A Detoxifying Enzyme Acting as an Undercover Toxifying Enzyme

Janda

Nepveu

Calamini

et al. 2020

Molecular Pharmacology

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N-ribosyldihydronicotinamide:quinone oxidoreductase 2 (NQO2/ QR2, Enzyme Commission number 1.10.99.2) is a cytosolic enzyme, abundant in the liver and variably expressed in mammalian tissues. Cloned 30 years ago, it was characterized as a flavoenzyme catalyzing the reduction of quinones and pseudoquinones. To do so, it uses exclusively N-alkyl nicotinamide derivatives, without being able to recognize NADH, the reference hydrure donor compound, in contrast to its next of a kind, NAD(P)H:quinone oxidoreductase 1 (NQO1). For a long time both enzymes have been considered as key detoxifying enzymes in quinone metabolism, but more recent findings point to a more toxifying function of NQO2, particularly with respect to ortho-quinones. In fact, during the reduction of substrates, NQO2 generates fairly unstable intermediates that reoxidize immediately back to the original quinone, creating a futile cycle, the byproducts of which are deleterious reactive oxygen species. Beside this peculiarity, it is a target for numerous drugs and natural compounds such as melatonin, chloroquine, imiquimod, resveratrol, piceatannol, *

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Discovery of potent 4-aminoquinoline hydrazone inhibitors of NRH:quinoneoxidoreductase-2 (NQO2)

Cited by 12 publications

References 34 publications

Anticancer Activity of Erianin: Cancer-Specific Target Prediction Based on Network Pharmacology

Anticancer Activity of Erianin: Cancer-Specific Target Prediction Based on Network Pharmacology

Curcumol Overcomes TRAIL Resistance of Non‐Small Cell Lung Cancer by Targeting NRH:Quinone Oxidoreductase 2 (NQO2)

Molecular Pharmacology of NRH:Quinone Oxidoreductase 2: A Detoxifying Enzyme Acting as an Undercover Toxifying Enzyme

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