Tentative identification of gefitinib metabolites in non-small-cell lung cancer patient plasma using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry

Wang, Chao; Zhang, Jingui; Zhou, Simin; Yu, Limei; Han, Fangxuan; Ren, Ling; Jin, Ling

doi:10.1371/journal.pone.0236523

Cited by 12 publications

(12 citation statements)

References 22 publications

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“…the O-demethylation, oxidative defluorination, and oxidation of gefitinib were among the metabolic pathways identified in this study, as shown in Figure 34. Wang et al investigated the metabolism of gefitinib in NSCLC patients [92]. Eighteen metabolites were tentatively identified in human plasma.…”

Section: Metabolismmentioning

confidence: 99%

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Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

et al. 2021

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Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

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Section: Metabolismmentioning

confidence: 99%

“…Eighteen metabolites were tentatively identified in human plasma. Among these metabolites, M7 [92]. Eighteen metabolites were tentatively identified in human plasma.…”

Section: Metabolismmentioning

confidence: 99%

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

et al. 2021

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“…However, it was accompanied by a further decrease in solubility (HT sol pH 6.8 = <0.001 g/L). Morpholines are common motifs in drugs; however, they are known to lead to potential metabolic liabilities. , To reduce this risk, we explored carbon-connected residues at position C5 of the imidazolopyridine core. A small i Pr group provided a potent and soluble compound ( 14 ) (pS6 IC 50 = 31 nM and HT sol pH 6.8 = >0.34 g/L) with low CYP3A4 TDI and high selectivity over ATR (pCHK1 IC 50 = >50 μM), but increased PDE4D (IC 50 = 4.8 μM) inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in-vacuo. The crude material was purified by silica gel chromatography (0−40% EtOAc in heptane) to afford (R)-4-( 6 ( [4,5-c]pyridin-4-yl)morpholine (28). To a microwave vial under N 2 were added NaOtBu (366 μL, 0.731 mmol), 27 (200 mg, 522 μmol), (S)-3-methylmorpholine (74 mg, 731 μmol), RuPhos Pd G1 (19.0 mg, 26 μmol), and 1,4dioxane (5.2 mL), and the reaction mixture was stirred at 110 °C for 3 h under microwave radiation.…”

Section: R)-3-methyl-4-(6-((s)-3-methylmorpholino)-2-(1h-pyrazol-3-yl...mentioning

confidence: 99%

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes

Bonazzi¹,

Gray²,

Thomsen³

et al. 2023

J. Med. Chem.

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The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure−activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.

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“…In addition, there is emerging evidence that omega-3 fatty acids may play an integral role in linking the microbiome and immune system by regulating inflammation [ 27 ]. A recent study finds a link between microbiota and response to Sutent [ 28 ] as well as Iressa [ 29 ]. Therefore, NuF may increase the efficacy of TKIs by regulating the gut microbiota.…”

Section: Discussionmentioning

confidence: 99%

Fish Oil, Se Yeast, and Micronutrient-Enriched Nutrition as Adjuvant Treatment during Target Therapy in a Murine Model of Lung Cancer

Wang

Hsia

et al. 2021

Marine Drugs

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Despite the effectiveness of primary treatment modalities for cancer, the side effects of treatments, medication resistance, and the deterioration of cachexia after disease progression lead to poor prognosis. A supportive treatment modality to overcome these limitations would be considered a major breakthrough. Here, we used two different target drugs to demonstrate whether a nutraceutical formula (fish oil, Se yeast, and micronutrient-enriched nutrition; NuF) can interfere with cancer cachexia and improve drug efficacy. After Lewis lung cancer (LLC) tumor injection, the C57BL/6 mice were orally administered targeted therapy drugs Iressa and Sutent alone or combined with NuF for 27 days. Sutent administration effectively inhibited tumor size but increased the number of lung metastases in the long term. Sutent combined with NuF had no significant difference in tumor weight and metastasis compare with Sutent alone. However, NuF slightly attenuated metastases number in lung may via mesenchymal marker N-cadherin suppression. NuF otherwise increased epithelial-like marker E-cadherin expression and induce NO-mediated intrinsic apoptotic pathway in tumor cells, thereby strengthening the ability of the targeted therapy drug Iressa for inhibiting tumor progression. Our results demonstrate that NuF can promote the anticancer effect of lung cancer to targeted therapy, especially in Iressa, by inhibiting HIF-1α and epithelial-mesenchymal transition (EMT) and inducing the apoptosis of lung cancer cells. Furthermore, NuF attenuates cancer-related cachectic symptoms by inhibiting systemic oxidative stress.

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Tentative identification of gefitinib metabolites in non-small-cell lung cancer patient plasma using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry

Cited by 12 publications

References 22 publications

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes

Fish Oil, Se Yeast, and Micronutrient-Enriched Nutrition as Adjuvant Treatment during Target Therapy in a Murine Model of Lung Cancer

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