JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Yuying Wang,Quanwei Yu,Xiongqi Yang,Lingling Ma,Ridong Huang,Hai Chen,Zhonghua Jiang,Zhenru Wu,Chengyong Wu,Xuemei Deng,Jing Wang,Weimin Li,Yang He
The tertiary C797S mutation in the EGFR tyrosine kinase domain disrupts osimertinib binding, driving resistance in NSCLC. We designed a series of novel diaminopyrimidine derivatives to establish the interaction with Ser797. H8b potently inhibited EGFRL858R/T790M/C797S kinase with an IC50 of 3.86 nM (30-fold lower than osimertinib) and suppressed both double mutant NCI-H1975 and triple mutant H1975-M3 cells with IC50s of 0.03 μM and 0.57 μM (14- and 11-fold reductions over osimertinib, respectively). Cocrystal X-ray analysis revealed that H8b forms a “two-point tethering” in the ATP pocket with a hydrogen bond between its dichloropropionamide oxygen and Ser797, complemented by a hydrogen bond between terminal N of the piperazine ring and Phe795. Mechanistically, H8b suppressed EGFR phosphorylation and downstream AKT, STAT3, and MAPK signaling, inhibiting proliferation, invasion, and migration. In vivo, H8b achieved 71.15% tumor inhibition in H1975-M3 xenografts. This study identifies H8b as a promising EGFR-TKI overcoming C797S-mediated resistance.
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高影响因子
CARBOHYDRATE RESEARCH
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2025
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IF 2.5
Pengxiao Hou,Chaowei Tang,Wei Zhao,Zhilong Li
Non-small cell lung cancer (NSCLC) has a poor prognosis due to late diagnosis and high metastasis, while existing agents like Cucurbitaceae-derived Compound 1 are limited by low solubility, poor targeting, and high normal cell toxicity. This study aimed to construct a fluorinated hyaluronic acid nanocarrier (HA-2@1) to load Compound 1, improving its solubility/biocompatibility, enabling NSCLC-targeted delivery, and enhancing therapeutic efficacy. In vitro experiments included pH-responsive drug release testing, fluorescence spectroscopy for carrier-drug interactions, and CCK-8 cytotoxicity assays on A549 (NSCLC) and BEAS-2B (normal lung) cells, compared with free Compound 1. Results showed: HA-2@1 released 75% of Compound 1 at pH 5.0 (tumor microenvironment) vs. 43% at pH 7.4 (physiological condition) within 120 h; Compound 1 loading reduced HA-2 fluorescence by 26% (intermolecular quenching) with further aggregation-driven quenching at 100 μg/mL; HA-2@1 decreased A549 viability by 25% at 48 h, and its toxicity to BEAS-2B cells (7% at 200 μg/mL) was far lower than free Compound 1 (53%). In conclusion, HA-2@1 offers targeted delivery, fluorescence tracking, low toxicity, and efficient release, providing a promising nano-strategy for NSCLC therapy and a reference for natural product carrier optimization.
研究领域:
肿瘤学
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药剂学
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纳米医学
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分子药理学
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生物材料
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药物递送系统
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
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IF 8.3
Cheng Hu,Jia-Qi Zhang,Xiao-Yu Zhuang,Zhen-Duo Zhao,Xiao-Jing Qian,Ying Chen
Purpose To study the pharmacological effects of solasonine (Sol) in inhibiting non-small cell lung cancer (NSCLC) metastasis. Methods The pharmacological effects of solasonine were examined in vitro by continuous induction of NSCLC cells by no treatment, or TGF-β, or creatine. Cell migration and invasion were assessed via wound healing and transwell assays, and the levels of epithelial-mesenchymal transition (EMT) markers were determined using immunofluorescence and Western Blot. Solasonineʼs ability to bind to TGF-β and creatine transferases and isoenzymes was assessed by TCGA, KMPLOT database, cellular thermal shift assay (CETSA), and molecular docking assay. In vivo , two types of NSCLC cells were injected into mice using the tail vein. Solasonineʼs effect on tumor metastasis was determined using in vivo fluorescent probes, hematoxylin-eosin staining assay, and immunofluorescence. Results Unlike traditional therapies targeting TGF-β receptors, Sol was shown to inhibit NSCLC metastasis through a novel mechanism independent of TGF-β signaling. Creatine was found to promote NSCLC metastasis in vitro by enhancing cell migration, invasion, and EMT-related protein expression, and in vivo by increasing metastasis to the liver. These effects were mediated by the activation of Smad2 phosphorylation and EMT independently of TGF-β. Sol effectively counteracted these effects by targeting guanidinoacetate methyltransferase (GATM) with high binding affinity, thereby suppressing the TTK-mediated Smad2 pathway and significantly reducing metastasis to the lungs and liver, as confirmed by HE staining and fluorescence imaging. Conclusions This study identifies solasonine as a novel inhibitor of NSCLC metastasis, acting through the GATM and Smad2 pathways to counter creatine-induced metastasis. These findings underscore the potential of Sol as a therapeutic candidate for metastatic NSCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2019
·Vol. 8
·期 2
·332-342
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IF 5.047
Huihui Shi,Ming Xu,Jianhua Zhu,Yang Li,Zhiyu He,Yuxia Zhang,Qunwei Xu,Yimin Niu,Yang Liu
Recently, ultra-small platinum nanoparticles (USPtNs) have been found that can kill cancer cells by leaching Pt ions into acidic organelles, such as cell endosomes or lysosomes. Unfortunately, tumor-specific accumulation is difficult to achieve with such platinum nanodrugs of less than 5 nm due to their short half-life in vivo and broad range of toxicity to normal tissues. Programmable multi-drug release for combinational chemotherapy by hierarchical nanostructures provides a promising solution for cancer-targeted therapy. Herein, we demonstrated a pH/redox dual stimuli-responsive clustered nanoparticle as a vehicle for simultaneously delivering USPtNs and gemcitabine (GEM) to treat non-small-cell lung cancer. The clustered nanoparticle (denoted as GP-NA) was composed of disulfide-bond-containing GEM-grafted copolymers (PEG-b-P(LL-g-GEM)), pH-sensitive polypeptides (OAPI), and USPtNs. Such a hybrid nanosystem completes multiple tasks inside cancer cells, which include the generation of cytotoxic Pt ions in response to lysosomal acidic environments and the subsequent release of GEM in cytoplasmic reduction environments. Compared with non-acid-sensitive nanoparticles or free drugs, GP-NA exhibited cumulative and enhanced anti-tumor efficacy in vivo, which may be attributed to the simultaneous inhibition of ribonucleotide reductase and DNA replication in nuclei by the GEM and Pt ions. Together, our work provides a promising strategy in the co-delivery of USPtNs and GEM for precision cancer chemotherapy.
研究领域:
药学
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肿瘤学
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纳米医学
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DOI
PubMed
高影响因子
Molecular Cancer
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2022
·Vol. 21
·期 1
·1-17
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IF 41.444
Pan Zhenzhen,Wang Kai,Wang Xiniao,Jia Zhirong,Yang Yuqi,Duan Yalei,Huang Lianzhan,Wu Zhuo-Xun,Zhang Jian-ye,Ding Xuansheng
Background The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.Methods EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.Results Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.Conclusion sOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Biosensors-Basel
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2023
·Vol. 13
·期 6
·647
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IF 5.4
Jingbo Zhang,Quancheng Chen,Xuemin Gao,Qian Lin,Ziqin Suo,Di Wu,Xijie Wu,Qing Chen
In this study, a label-free and antibody-free impedimetric biosensor based on molecularly imprinting technology for exosomes derived from non-small-cell lung cancer (NSCLC) cells was established. Involved preparation parameters were systematically investigated. In this design, with template exosomes anchored on a glassy carbon electrode (GCE) by decorated cholesterol molecules, the subsequent electro-polymerization of APBA and elution procedure afforded a selective adsorption membrane for template A549 exosomes. The adsorption of exosomes caused a rise in the impedance of the sensor, so the concentration of template exosomes can be quantified by monitoring the impedance of GCEs. Each procedure in the establishment of the sensor was monitored with a corresponding method. Methodological verification showed great sensitivity and selectivity of this method with an LOD = 2.03 × 103and an LOQ = 4.10 × 104particles/mL. By introducing normal cells and other cancer cells derived exosomes as interference, high selectivity was proved. Accuracy and precision were measured, with an obtained average recovery ratio of 100.76% and a resulting RSD of 1.86%. Additionally, the sensors’ performance was retained at 4 °C for a week or after undergoing elution and re-adsorption cycles seven times. In summary, the sensor is competitive for clinical translational application and improving the prognosis and survival for NSCLC patients.Keywords:exosomes;molecular imprinted polymers (MIPs);antibody-free;impedimetric sensor
研究领域:
生物传感器
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癌症诊断
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纳米技术
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电化学
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DOI
PubMed
高影响因子
iScience
·
2026
·Vol. 29
·期 7
·
IF 4.5
Wujin Li,Changjian Lin,Hang Xu,Wenxiang Yue,Yi Xu,Baosong Xie,Daxuan Wang
Sulforaphane (SF) suppresses NSCLC metastasis by modulating miR-616-5p, which is transcriptionally upregulated by the oncogenic transcription factor SPI1. However, the roles of SF, SPI1, and miR-616-5p in NSCLC metastasis remain unclear. In this study, we found that SPI1 expression in NSCLC tissues positively correlated with miR-616-5p levels, and that SPI1 transcriptionally regulated miR-616-5p to promote NSCLC cell invasion and migration. Further analysis showed that SF directly binds SPI1, inhibiting its activity and downregulating miR-616-5p expression, thereby attenuating NSCLC metastasis. However, the poor stability of SF limits its clinical application. To address this, we developed a mesoporous silica nanoparticle (MSN)-based delivery system modified with hyaluronic acid and folic acid (MSNs@SF-HA-FA), which exhibited good stability, enhanced cellular uptake, and improved tumor targeting and anti-metastatic efficacy in NSCLC xenograft models. Collectively, our findings reveal the SPI1/miR-616-5p axis drives NSCLC metastasis and show that MSNs@SF-HA-FA enhances SF′s anti-metastatic effect, highlighting its clinical potential.
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PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
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IF 18.5
Shuaijun Li,Caiting Meng,Qian Hao,Luyao Dai,Jiahong Shi,Ji Xu,Xin Zhou,Sitong Zhao,Jinfan Yang,Huafeng Kang,Yuzhu Hou,Mingzhen Zhang,Xiaobin Ma,Mingqian Tan,Hao Wu
Immune checkpoint blockade (ICB) therapy has emerged as a promising approach in clinical oncology. For brain metastases, the presence of the robust blood–brain barrier (BBB) and potential immune-related adverse events (irAEs) pose significant challenges. Here, a multistage-responsive antibody-delivery strategy is developed for non-small cell lung cancer (NSCLC) brain metastases, with the ultra-pH sensitivity borate bonds. The antibody-delivery nanoformulation (MB-aPDL1) is able to maintain the “silent state” in health tissue, cross the BBB/BTB by the GLUT1-mediated transcytosis, release the functionalized aPDL1 responsively, and promote the aPDL1 tumor-anchoring. In the in vivo tumor region, the MB-aPDL1 rapidly releases the activated BPA 6 -aPDL1, which successfully anchors to the tumor cells and improves the efficiency of ICB therapy. The two in vivo ICB therapy studies show a significant tumor growth inhibition from the MB-aPDL1 with an encouraging cure rate of 20% for the NSCLC brain metastases, due to enhanced immune response in tumor, commendably with less behavioral adverse reactions and liver damage. Taken together, this antibody-delivery strategy holds substantial potential for application in clinical treatment of brain metastases.
研究领域:
肿瘤学
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药理学
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生物医学工程
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神经科学
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免疫学
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DOI
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 12
·期 8
·2202287
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IF 11.092
Lei Guo,Zhaode Mu,Min Qing,Jing Zhou,Huizhen Li,Lulu Wang,Muyue Zhong,Lijuan Bai
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with substantial morbidity and mortality. Herein, a new signal-on electrochemiluminescence (ECL) immunosensor based on multiple amplification strategies is constructed for ultrasensitive detection of cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) biomarker related to NSCLC. Polyethyleneimine (PEI) functionalized MXene is decorated with NiMn layer double hydroxide (NiMn LDH) to form MXene-PEI-NiMn LDH composite. Specially, the La-MOF@ZIF-67 bimetallic organic framework (named as LZBM) and MXene-PEI-NiMn LDH both served as coreaction accelerators to improve the ECL emission of the luminol-H 2 O 2 system. To be specific, Au nanoparticles (AuNPs) coated MXene-PEI-NiMn LDH is applied to immobilize primary CYFRA21-1 antibody (Ab 1 ), while AuNPs decorated LZBM was used for the loading of luminol and secondary CYFRA21-1 antibody (Ab 2 ) to form tracer label. Therefore, the ECL signal of the sandwich-type immunosensor is significantly enhanced due to the high loading capability for luminol and the synergistic catalytic ability for the decomposition of H 2 O 2 into reactive oxygen species (ROS). Under the optimal experimental conditions, the ECL immunosensor exhibited good analytical performances for CYFRA21-1 detection with a wide linear range (100 fg mL −1 −100 ng mL −1 ) and a low limit of detection (85.20 fg mL −1 ), providing a promising method for early diagnosis of NSCLC.
研究领域:
分析化学
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生物医学工程
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癌症诊断
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纳米技术
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生物传感器
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PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2024
·
IF 2.8
Yunfeng Zhu,Fangkai Wang,Xin Wang,Ya Cheng,Xingyu Wang,Ali Fan,Jiawei Chang
Taletrectinib is a potent selective ROS and pan-NTRK tyrosine kinase inhibitor (TKI) and has been developed to treat non-small cell lung cancer (NSCLC). To facilitate pharmacokinetic and toxicokinetic studies of taletrectinib, we developed a procedure for ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to detect the plasma level of taletrectinib in dogs. This assay procedure was validated in compliance with FDA guidance. The dog plasma samples were spiked with internal standard (IS), followed by protein precipitation, and analyzed using a Waters ACQUITY BEH C 18 column coupled to a Thermo triple quadrupole mass spectrometer. Separation was executed using the acetonitrile-0.1 % formic acid solution with gradient elution, at a flow rate of 0.4 mL/min. Taletrectinib and IS were monitored by multiple reaction monitoring (MRM) with m / z 406.2 > 349.2 and m / z 441.2 > 138.1, respectively. The procedure demonstrated excellent linearity with a correlation coefficient greater than 0.999 within the concentration range of 0.2–200 ng/mL. The inter- and intra-day accuracy ranged from −5.25 % to 5.26 %, and the precision was below 6.39 %. Acetonitrile-mediated protein precipitation showed high extraction efficiency and a recovery above 85 %. The procedure was then applied to quantify taletrectinib in beagle dog plasma after oral and intravenous doses and achieved success. The obtained pharmacokinetic parameters indicated high bioavailability of taletrectinib (>85 %) and extensive tissue distribution (>40 L/kg).
研究领域:
药理学
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肿瘤学
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分析化学
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DOI
PubMed
高影响因子
Journal of Cancer
·
2017
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IF 2.916
Mingtong Ye,Sufan Wang,Ting Wan,Rui Jiang,Yun Qiu,Lei Pei,Nengzhi Pang,Yuanling Huang,Yufeng Huang,Zhenfeng Zhang,Lili Yang
Efficacy of EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, to treat human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR is not persistent due to drug resistance. Reprogramming in energy (especially glucose) metabolism plays an important role in development and progression of acquired resistance in cancer cells. We hypothesize that glucose metabolism in EGFR-TKI sensitive HCC827 cells and erlotinib-resistant sub-line of HCC827 (which we name it as erlotinib-resistant 6, ER6 cells in this study) is different and targeting glucose metabolism might be a treatment strategy for erlotinib-resistant NSCLCs. In this study, we found increased glucose uptakes, significant increase in glycolysis rate and overexpression of glucose transporter 1 in ER6 cells compared to its parental cells HCC827. We also found AKT and autophagy of ER6 cells were more activated than HCC827 cells after glucose starvation. Combining glucose deprivation and AKT or autophagy inhibitor could synergize and overcome the acquired resistance against EGFR-targeted therapy for NSCLCs. Our data suggest that the combinations of inhibitors of AKT or autophagy together with glucose deprivation could be novel treatment strategies for NSCLC with acquired resistance to targeted therapy.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
CANCER LETTERS
·
2024
·
IF 9.1
Erbao Zhang,Qi Sun,Chang Zhang,Huimin Ma,Jing Zhang,Yue Ding,Guoqing Wang,Chen Jin,Chenying Jin,Yating Fu,Caiwang Yan,Meng Zhu,Cheng Wang,Juncheng Dai,Guangfu Jin,Zhibin Hu,Hongbing Shen,Hongxia Ma
Approximately 51 non-small-cell lung cancer (NSCLC) risk loci have been identified by genome-wide association studies (GWASs). We conducted a high throughput RNA-interference (RNAi) screening to identify the candidate causal genes in NSCLC risk loci. KIAA0391 at 14q13.1 had the highest score and could promote proliferation and metastasis of NSCLC in vitro and in vivo . We next prioritized rs3783313 as a causal variant at 14q13.1, by integrating a large-scale population study consisting of 27,120 lung cancer cases and 27,355 controls, functional annotation, and expression quantitative trait locus (eQTL) analysis. Then we found that rs3783313 could facilitate a promoter-enhancer interaction to upregulate KIAA0391 expression by affecting the affinity of transcription factor NFYA. Mechanistically, KIAA0391 knockdown dramatically influenced pyroptosis-related pathways and increased the expression of CASP1. And KIAA0391 transcriptionally repressed CASP1 by binding to SMAD2 and induced an anti-pyroptosis phenotype, promoting tumorigenesis of NSCLC, which provides new insights and potential target for NSCLC.
研究领域:
肿瘤学
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基因组学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）