TOXICOLOGY LETTERS
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2021
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IF 4.374
Zhe Wang,Xiaoyu Wang,Zhen Wang,Yaqin Jia,Yuyi Feng,Lili Jiang,Yangliu Xia,Jun Cao,Yong Liu
Osimertinib is the only third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) approved by Food and Drug Administration (FDA). This study aimed to know the inhibitory effect of osimertinib on human UDP-glucosyltransferases (UGTs) and human liver microsomes (HLMs), as well as to identify its potential to cause drug-drug interaction (DDI) arising from the modulation of UGT activity. High inhibitory effect of osimertinib was shown towards UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A10, 2B7 and 2B15. Especially, osimertinib exhibited competitive inhibition against UGT1A1 with a K i,u of 0.87 ± 0.12 μM. It also noncompetitively inhibited SN-38 glucuronidation in pooled HLMs with a K i,u of 3.32 ± 0.25 μM. Results from quantitative prediction study indicated that osimertinib administered at 80 mg/day may result in a 4.83 % increase in the AUC of drugs mainly metabolized by UGT1A1, implying low risk of DDI via liver metabolism. However, the ratios of [ I ] gut / K i,u are much higher than 11 in HLMs and recombinant UGT1A1, indicating a risk for interaction in intestine. The effects of osimertinib on intestinal UGT should be paid more attention on to avoid unnecessary clinical DDI risks.
研究领域:
药理学
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临床医学
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PubMed
高影响因子
BIOPHARMACEUTICS & DRUG DISPOSITION
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2023
·Vol. 44
·期 2
·165-174
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IF 2.1
Xuyi Zhan,Shaoyin Bao,Xumei Li,Shaojun Zhou,Maha Raja Dahar,Nengming Lin,Xiugui Chen,Chengshan Niu,Kaige Ji,Yusheng Wu,Kui Zeng,Zhihua Tang,Lushan Yu
Osimertinib is a highly selective third-generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non-small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib-d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib-d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (C max ) compared with the osimertinib in rats and human body.
研究领域:
药理学
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肿瘤学
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生物化学
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PubMed
高影响因子
BMC Pharmacology & Toxicology
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2026
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IF 3.5
Ma Tingnan,Yuan Tao,Hou Yingying,Liu Maoyu,Zhang Yaru,Shi Jianyou,Zhong Lei
Background The introduction of EGFR inhibitors has revolutionized the management of NSCLC, leading to a significant extension of survival in the target patient population. Unfortunately, acquired resistance appears to be unavoidable, which restricts the use of EGFR-TKIs in the clinic. EGFR C797S represents a novel resistant mutation after treatment with the latest generation of EGFR inhibitor Osimertinib. Consequently, developing next-generation EGFR-TKIs targeting such resistant mutations is strongly demanded. Methods Osimertinib-resistant NSCLC cell lines were constructed by transfecting EGFR del19/T790M/C797S or EGFR L858R/T790M/C797S lentiviral plasmids into NSCLC PC-9 cells, followed by puromycin screening. The drug screening was conducted in a drug repurposing compound library provided by TargetMol. The hit compound (CZC54252) was validated by kinase inhibition, western blot, and molecular docking assays. Its role in overcoming Osimertinib resistance was further evaluated by cellular viability, proliferation, and apoptosis tests. Finally, animal studies were conducted in xenograft models to verify the anti-NSCLC effects of CZC54252 in vivo. Results The cell models resistant to Osimertinib have been successfully established, and CZC54252 was screened as a hit compound that could overcome Osimertinib resistance, with IC 50 values of 0.24 ± 0.06 µM and 0.27 ± 0.09 µM on PC-9 del19/T790M/C797S and PC-9 L858R/T790M/C797S cells, respectively, which were significantly lower than those of Osimertinib (2.1 ± 0.32 µM and 2.8 ± 0.37 µM, respectively). CZC54252 displayed potent inhibitory activity on EGFR del19/T790M/C797S (IC 50 : 1.66 nM) and EGFR L858R/T790M/C797S (IC 50 : 2.92 nM), and significantly repressed EGFR phosphorylation in western blot assay. Additionally, the pharmacodynamics studies demonstrated that CZC54252 moderately suppressed cell proliferation and induced cell apoptosis both in vitro and in vivo. Notably, not all drug candidates targeting the same molecular pathways as CZC54252 showed activity in the screening, indicating that CZC54252 may overcome Osimertinib resistance by directly targeting EGFR C797S triple mutations rather than its original targets. Conclusion These data indicate that CZC54252 represents a promising lead compound for overcoming Osimertinib resistance by targeting EGFR C797S , which provides a chemical basis for the development of novel fourth-generation EGFR inhibitors. Graphical The alternative text for this image may have been generated using AI.
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高影响因子
LIFE SCIENCES
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2026
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IF 5.1
Zhongquan Song,Yanmei Zhu,Surong Fang,Shuhua Han
Aims The EGFR-C797S mutation is the main cause of Osimertinib resistance. No effective treatment regimen is currently available for patients harboring EGFR-activation mutation/T790M/cis-C797S triple mutations. Materials and methods Nine patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activation mutation/T790M/cis-C797S mutation were investigated. After Osimertinib resistance, these patients were treated with Endostar combination with Osimertinib. Network pharmacology and molecular dynamics simulations were used to clarify active sites of Endostar and the effect on protein conformation. In vivo and in vitro , EGFR L858R-T790M-C797S/H1975 cells were used to investigate the efficacy of co-treatment. Key findings Two patients achieved partial response (PR), six achieved stable disease (SD) and one had progressive disease (PD) at the 6-month efficacy assessment of co-treatment, resulting in an objective response rate (ORR) of 66.7% and a disease control rate (DCR) of 88.9%. These patients achieved a median progression-free survival (PFS) of 8.9 months and a median overall survival (OS) of 18.5 months, and no patients experienced grade III or IV adverse events. Endostatin, the active ingredient of Endostar, bound EGFR to “pseudo” mediate EGFR signaling pathway, and the introduction of Endostar enhanced the binding of Osimertinib to EGFR L858R/T790M/C797S protein. In vitro and in vivo experiments have found the co-treatment restored sensitivity to Osimertinib. Moreover, the combination therapy significantly inhibited the activation of the EGFR signaling pathway and tumor neovascularization. Significance This work demonstrated for the first time that Endostar enhanced the antitumor efficacy of Osimertinib, offering a potential therapeutic approach for patients harboring triple mutations.
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高影响因子
International Journal of Analytical Chemistry
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2020
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IF 1.678
Zhenzhen Ying,Jingyao Wei,Ruijuan Liu,Fang Zhao,Yifang Yu,Xin Tian
Osimertinib is a novel oral, potent, and irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for treatment of advanced T790M mutation-positive advanced non-small cell lung cancer, which is commonly combined with ginsenoside Rg3 in clinic to enhance the efficacy and minimize adverse reactions. In the present study, a highly sensitive UPLC-MS/MS method was established and validated for analysis of osimertinib in rat plasma according to US FDA guideline. Separation was performed on a C18 (2.1 × 50 mm, 2.6 μm) column using a gradient elution of ammonium formate (10 mM) with 0.1% formic acid buffer (A) and ACN (B) at a flow rate of 0.2 mL/min. Detection was carried out on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization in the MRM mode. The method was validated over a concentration range of 1–400 ng/mL for osimertinib. The intra- and interday accuracy and precision values were within ±15%. No significant degradation occurred under the experimental conditions in stability assays. There was a further investigation on the effects of multiple doses of ginsenoside Rg3 on the pharmacokinetics of osimertinib in rats for the first time. The results implied that osimertinib exhibited a slow absorption and moderate-rate elimination in rats following oral administration. Coadministeration with ginsenoside Rg3 (5 mg/kg, 7 days, i.g.) may have no effect on the pharmacokinetics of osimertinib in rats. The results provide a reference for the clinical concomitant medications of Rg3 and osimertinib.
研究领域:
药物分析
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肿瘤学
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药理学
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PubMed
高影响因子
Scientific Reports
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2026
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IF 4.9
He Guangzhao,Wu Jing,Bi Yanzhi,Fu Cong,Yang Yanchu,Zu Yuanyuan,Huo Dan,Yu Jingping
Diosmectite is commonly used in clinical practice to manage osimertinib-induced diarrhea, but its impact on osimertinib absorption remains unclear. Eighteen male Sprague–Dawley rats were randomly assigned to three groups (n=6/group): control (osimertinib alone), co-administration (osimertinib immediately followed by diosmectite), and delayed-administration (diosmectite 0.5-hour after osimertinib). Blood samples were collected from the jugular vein at predetermined time points (0.25, 0.5, 1, 2, 4, 6, 8, and 24 h) after osimertinib administration. Plasma osimertinib concentrations were measured using a fully validated LC-MS/MS. Pharmacokinetic parameters were calculated using noncompartmental analysis. Compared with controls, co-administration reduced Cmax by 91.6% (84.8 ± 19.4 vs. 7.14 ± 2.15 ng·mL-1, P<0.05) and AUClast by 94.4% (670 ± 353 vs. 37.8 ± 9.7 h·ng·mL-1, P<0.05). Delayed-administration reduced Cmax by 38.0% (84.8 ± 19.4 vs. 52.6 ± 22.8 ng·mL-1, P<0.05) and AUClast by 66.3%(670 ± 353 vs. 226 ± 88 h·ng·mL-1, P<0.05). Diosmectite markedly reduces the oral absorption of osimertinib in rats. Delaying diosmectite by 0.5-hour partially but incompletely restores absorption. Clinical studies are needed to further verify this interaction.
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高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2017
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IF 2.93
Hongying Gao,Zimo Yang,Xinglin Yang,Yu Rao
Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N -oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1 – 6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2 , the newly synthesized N -oxide metabolite in N , N , N ′-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.
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PubMed
高影响因子
Cell Communication and Signaling
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2026
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IF 8.9
Qiu Yueping,Liu Yijie,Ding Haiying,Xin Wenxiu,Lu Shuanghui,Hu Yan,Chen Jing,Weng Qinjie,Wang Jiajia,Fang Luo
Osimertinib is a first-line treatment for advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR)-sensitive mutations; however, the severe hepatotoxicity of osimertinib is a challenge that has attracted attention. In this study, we found that osimertinib directly caused hepatocyte damage, with cells showing morphological features of vacuolization after treatment. Using transmission electron microscopy and other analytical techniques, we found that excessive activation of the autophagy-lysosome pathway was the main cause of cell vacuolation. Mechanistically, osimertinib causes dephosphorylation of transcription factor EB (TFEB), leading to its translocation into the nucleus to exert transcriptional regulatory functions. TFEB in the nucleus induces autophagy and lysosome biogenesis, thereby causing excessive activation of the autophagy-lysosome pathway subsequently leading to vacuolation-associated cell death. Through this study, we have identified S-adenosyl-L-methionine as a clinical hepatoprotective agent that could mitigate osimertinib-induced hepatocyte damage by inhibiting TFEB activation. Collectively, our findings not only lay the groundwork for addressing the clinical challenges posed by osimertinib hepatotoxicity but also broaden our understanding of drug-induced hepatocyte injury, thereby offering a novel research pathway for the study of drug-induced liver injury.
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高影响因子
American Journal of Translational Research
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2024
·Vol. 16
·期 12
·8008
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IF 1.7
Yalan Zuo,Peidan Yang,Ruixia Yang,Juan Hou,Rui Feng,Ping Liang,Jiang Liu
Objectives: The aim of this study was to establish an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the detection of osimertinib in rat plasma, lung and brain tissues. Methods: Forty-eight rats were randomly divided into an experimental group (receiving osimertinib at doses of 5, 8, and 10 mg/kg) and a control group. After continuous intragastric administration for 15 days, samples of blood, lung, and brain tissue were collected. Chromatographic separation was achieved using a BEH C18 column with gradient elution, employing a mobile phase of water (containing 0.1% (v/v) formic acid) and acetonitrile. The concentration of osimertinib in the samples was determined using an AB SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization (ESI+) and multiple reaction monitoring (MRM) mode. Results: A UPLC-MS/MS analytical method for determining osimertinib concentrations was successfully established and validated. A linear relationship was observed for osimertinib concentrations in plasma within the range of 1-300 ng/mL, and in lung and brain tissues within the range of 0.5-50 ng/mL. The selectivity, accuracy, precision, matrix effect, extraction recovery, and stability all meet the requirements of methodological validation criteria. Conclusions: A rapid and sensitive UPLC-MS/MS method was developed and validated for quantifying osimertinib concentrations in rat plasma, lung, and brain tissues, providing a valuable tool for pharmacokinetic and tissue distribution studies.
研究领域:
药理学
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分析化学
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药物代谢动力学
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高影响因子
International Journal of Electrochemical Science
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2024
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IF 1.3
Shiwen Zhao,Shu Du
This study presents the development of a molecularly imprinted polymer (MIP) based voltammetric sensor for the ultra-sensitive detection of osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor. The sensor was fabricated using a unique thia-bilane (S-BIL) functional monomer, which enhances the binding affinity and selectivity towards osimertinib. The pS-BIL MIP sensor exhibited a wide linear range (0.01–1000 nM), an extremely low detection limit (0.005 nM), and excellent selectivity, demonstrating its superiority over previously reported methods. The imprinting effect was confirmed through various characterization techniques, revealing the formation of specific recognition sites and improved electron transfer properties. The sensor displayed remarkable stability, retaining 95.2 % of its initial response after 30 days, and high reproducibility relative standard deviation (RSD) = 3.2 %, n = 5). Moreover, the pS-BIL MIP sensor was successfully applied to the determination of osimertinib in spiked human serum samples, with recoveries ranging from 96.5 % to 103.2 % and RSDs below 4.5 %. These findings highlight the immense potential of the developed sensor for the sensitive and reliable monitoring of osimertinib in clinical settings.
研究领域:
分析化学
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药物分析
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生物医学工程
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高影响因子
Cell Death Discovery
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2026
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IF 10.4
Zhen Shuman,Bai Xiaoxue,Liu Shutang,Zhang Haoran,Ren Xuejiao,Li Xiaoning,Dong Hua,Li Xiaoxu,Han Chun,Wang Lan
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved outcomes in EGFR-mutant lung adenocarcinoma (LUAD), yet acquired resistance to the third-generation inhibitor osimertinib remains inevitable. Although metabolic reprogramming is increasingly recognized as a driver of therapeutic resistance, the epigenetic consequences of lactate accumulation and their functional relevance in osimertinib resistance are poorly understood. Here we report that osimertinib-resistant LUAD cells exhibit enhanced glycolytic flux, increased intracellular lactate levels, and elevated histone H4 lysine 8 lactylation (H4K8la). Integrative transcriptomic analysis revealed significant enrichment of cell-cycle–associated pathways in resistant tumors, despite downregulation of canonical Cyclin B1 and Cyclin D1. Among the upregulated genes, GAS2L3 emerged as a prominent candidate. Genome-wide CUT&Tag profiling demonstrated enrichment of H4K8la at the GAS2L3 promoter, which was confirmed by ChIP–qPCR. Functionally, GAS2L3 overexpression accelerated S/G2–M progression and promoted proliferation under drug pressure, whereas its silencing induced cell-cycle arrest and restored osimertinib sensitivity both in vitro and in xenograft models. Notably, resistant cells displayed elevated P53 expression without induction of its canonical effector P21, indicating checkpoint uncoupling and a noncanonical mode of cell-cycle regulation. Mechanistically, glycolysis inhibition reduced H4K8la and GAS2L3 expression and partially re-sensitized resistant cells, while exogenous lactate restored H4K8la levels and resistance phenotypes, establishing a metabolically driven epigenetic circuit. Clinically, high GAS2L3 expression was associated with shorter progression-free survival in osimertinib-treated patients. Collectively, our findings identify a glycolysis–H4K8la–GAS2L3 axis that drives noncanonical cell-cycle reprogramming independently of classical Cyclin–CDK activation, thereby promoting acquired osimertinib resistance. These results uncover a metabolism-epigenetics–cell cycle interface that may represent a therapeutic vulnerability in EGFR-mutant LUAD.
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高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2018
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IF 2.881
Ping Zhou,Gang Chen,Minqi Gao,Jiaquan Wu
Osimertinib has been approved as a first-line treatment for non-small-cell lung cancer (NSCLC) patients whose tumor carries EGFR activation and / or resistant mutations. To mitigate Osimertinib’s toxicity caused by AZ5104, the N-demethylation metabolite of Osimertinib, we designed and synthesized a series of Osimertinib analogs with different headpieces. In vitro and in vivo analysis rendered a potential clinical candidate C-005 which had pyrrolo-pyridine headpiece. Biochemically, C-005 and its main human hepatocyte metabolite showed over 30 fold selectivity of L858R/T790M mutant EGFR over WT EGFR. Such selectivity profile was retained at cellular level. In general, C-005 is 2-14 fold more selective than Osimertinib in a panel of WT EGFR cancer cell lines. Furthermore, C-005 demonstrated robust antitumor efficacy and good tolerability in NCI-H1975, PC-9 and HCC827 xenograft mouse models, making it a potential candidate for human test in clinical.
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高影响因子
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