JOURNAL OF MEDICINAL CHEMISTRY
·
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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COLLOIDS AND SURFACES B-BIOINTERFACES
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2017
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IF 3.887
Wei Zhang,Jinlai Dong,Yang Wu,Peng Cao,Lina Song,Ming Ma,Ning Gu,Yu Zhang
In this study, Co 3 O 4 nanopolyhedrons, nanocubes, nanoplates and nanorods were synthesized and characterized. Furthermore, the peroxidase- and catalase-like activities of these Co 3 O 4 nanoparticles (NPs) were studied and influence of the exposed crystal planes was explored. According to their morphology and peroxidase-like activity, dimercaptosuccinic acid (DMSA) modified Co 3 O 4 nanopolyhedrons synthesized via coprecipitation method (Co 3 O 4 NHs) were selected as a proper candidate for the immunohistochemical (IHC) detection of epidermal growth factor receptor (EGFR) expression in non-small cell lung cancer (NSCLC) tissues. Bivalent cobalt ions were coupled to the carboxyls on the surface of the obtained Co 3 O 4 NHs so as to chelate the hexahistidine residues (His-Tags) at the C-terminal of EGFR single-domain antibodies (EGFR sdAbs). Finally, the as-obtained EGFR sdAbs-binding Co 3 O 4 NHs (Co 3 O 4 nanoprobes) were successfully applied to the detection of EGFR expression in NSCLC tissues.
研究领域:
材料科学
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纳米技术
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生物化学
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癌症研究
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分子生物学
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Scientific Reports
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2026
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IF 4.9
Liu Jiaying,Liu Nan,Ye Yiting,Ye Zhandong,Jiang Dongxu,Huang Song
Precancerous gastric lesions (PLGC) represent a critical transitional stage toward gastric cancer, yet effective interventions to halt progression remain limited. Vitexin, a naturally occurring flavonoid, exhibits anti-cancer potential; however, its molecular targets and mechanisms in PLGC have not been fully defined. This study aimed to elucidate the targets and mechanisms of vitexin against PLGC using an integrative strategy combining network pharmacology, molecular docking/molecular dynamics (MD), and cellular validation. Putative targets of vitexin and PLGC-associated genes were intersected to obtain 33 common targets, followed by protein–protein interaction network construction and pathway enrichment analyses. Molecular docking was performed against core targets, and MD simulations were conducted to assess the stability of the EGFR–vitexin complex. In vitro validation was carried out in MNNG-induced MC cells using cell viability, migration, and invasion assays, phase-contrast imaging, and immunofluorescence staining of EGFR and E-cadherin. Network analysis highlighted CCND1, EGFR, and ABL1 as central nodes and implicated oncogenic programs including cell-cycle regulation and PI3K–Akt signaling pathway. Docking suggested favorable binding of vitexin to the core targets. MD simulations further supported a stable binding mode of vitexin within the EGFR pocket over 100 ns with preserved global compactness; a late-stage conformational adaptation accompanied by hydrogen-bond network reorganization was observed without signs of global unfolding. Functionally, vitexin reduced MC cell viability in a dose-dependent manner, reaching ~ 50% inhibition at 20 μM, and significantly suppressed cell migration and invasion. Immunofluorescence demonstrated decreased EGFR expression and altered membrane localization, together with restored E-cadherin expression and membrane localization, suggesting a shift toward an epithelial phenotype. Vitexin inhibits PLGC-associated malignant phenotypes through multi-target modulation. Among the identified candidates, EGFR may serve as a putative and functionally relevant target, while modulation of EGFR-associated signaling together with restoration of E-cadherin may contribute to the reversal of EMT-related phenotypes. These findings provide mechanistic and structural support for the further preclinical evaluation of vitexin in preventing gastric cancer progression.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Wanqi Chen,Jiangbo Liang,Zhuoyan Wu,Xiaomei Shi,Mengjiao She,Rui Chen,Renshan Deng,Huan Zeng,Chengbo Liu,Ao Yu,Qiong Wu,Wenjie Mei
Targeting G-quadruplex (G4) DNA in oncogene promoters represents an emerging anticancer strategy. The epidermal growth factor receptor (EGFR) gene promoter contains a G4-forming sequence that epigenetically regulates EGFR transcription, making EGFR G4 DNA a promising therapeutic target. Here, we investigate the interaction of alkynyl-modified phenanthroimidazole derivatives ( 1 – 5 ) with this macromolecular structure. Through high-throughput molecular docking against multiple G4 targets (Bcl-2, c-Kit, EGFR, K-Ras), compound 5 (para-phenylethynyl-substituted) was identified as the most potent EGFR G4 DNA binder, with favorable binding energy and stable binding mode validated by molecular dynamics simulations. Biophysical analyses (UV–Vis/fluorescence titration, circular dichroism, isothermal titration calorimetry, PCR-stop assays) revealed that compound 5 binds EGFR G4 DNA with high affinity (K d = 1.15 × 10 −6 M), selectively stabilizes its parallel conformation, and inhibits DNA polymerase elongation. This stabilization leads to transcriptional repression of EGFR, as evidenced by dose-dependent downregulation of EGFR in HepG2 cells. Mechanistically, compound 5 induces G4-mediated DNA replication stress and damage, elevates ROS, activates p53 signaling, and modulates the PI3K/AKT/mTOR pathway, ultimately triggering ferroptosis. Notably, compound 5 exhibits superior anti-proliferative activity against HepG2 cells compared to doxorubicin (DOX) and Gefitinib, with markedly reduced cytotoxicity toward normal cells. In vivo efficacy was confirmed in a zebrafish xenograft model, where compound 5 significantly suppressed tumor proliferation. These findings establish compound 5 as a potent EGFR G4 DNA stabilizer that exerts multi-level anti-tumor effects through targeted modulation of this macromolecular structure, offering a promising lead for EGFR G4-directed liver cancer therapy.
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Chemical Biology & Drug Design
·
2023
·Vol. 103
·期 1
·e14408
·
IF 3
Xiao-Wen Nie,Ali Adnan Nasim,Xiao-Jun Yao,Xing-Xing Fan
The emergency of tyrosine kinase inhibitors has remarkably enhanced the clinical outcomes of cancer therapy, especially the use of EGFR inhibitors for non-small cell lung cancer (NSCLC). However, acquired resistance is inevitable after 8–12 months treatment. New agents or treatments are urgently required to resolve this problem. In this study, we identified that compound ZYZ384 can selectively inhibit the growth of gefitinib-resistant (G-R) lung cancer cells, without affecting that of normal lung epithelial cells. ZYZ384 induced G2 arrest in G-R NSCLC cells, decreasing the expression of Cyclin B1 and increasing the expression of P21. Meanwhile, ZYZ384 also induced apoptosis in NSCLC cells and correspondingly increased the expression of cleaved Caspase 3, 8, and 9 proteins. The expression of p-JNK, p-P38, and p-ERK were also increased in H1975 NSCLC cells treated with ZYZ384. Finally, we observed that the JNK inhibitor effectively reversed the pro-apoptotic effect of ZYZ384. In conclusion, ZYZ384 is a potential therapeutic agent to inhibit the growth of NSCLCs with EGFR mutations through activating JNK, which will help the development of related anticancer drugs.
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Journal of Thoracic Disease
·
2023
·
IF 2.5
Dianbao Zhang,Yukun Yang,Yixin Kang,Dongjie Xie,Xianfen Zhang,Jiqing Hao
Background An increasing amount of evidence has confirmed that the altered expression of microRNAs (miRNAs) is critical to the mechanism underlying primary and even acquired resistance to tyrosine kinase inhibitors (TKIs). However, studies on the linkage between the altered miRNAs expression and osimertinib resistance are few, and the effect of miRNAs in this context is still unclear. In the light of this, we hypothesized that the differential expression of multiple miRNAs is the driver in the osimertinib resistance process. Thus, the aim of our study was to find differentially expressed miRNAs in non-small cell lung cancer cells resistant to osimertinib. Methods An AZD9291(Osimertinib)-resistant cell line model was constructed, and the differential miRNAs between epidermal growth factor receptor (EGFR)-sensitive cell lines A549 and H1975 and the corresponding drug-resistant cell lines were identified via biosynthesis analysis. Results In the A549 osimertinib-resistant cell line, 93 miRNAs were upregulated and 94 miRNAs were downregulated. In the H1975 osimertinib-resistant cell line, 124 miRNAs were upregulated and 53 miRNAs were downregulated. Finally, 7 significantly different miRNAs were screened using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Conclusions This study on the mechanism of target therapy in lung cancer systematically and comprehensively examined the miRNAs involved in osimertinib resistance. It was found that miR-708-5p, miR-708-3p, miR-10395-3p, miR-7704 miR-34a-5p, miR-19b-1-5p, and miR-219a-5p may play key roles in osimertinib resistance.
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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PHARMACOLOGICAL RESEARCH
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2024
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IF 9.1
Yilan Huang,Siwei Wang,Xiaojun Zhang,Chen Yang,Sikai Wang,Hongxia Cheng,Aiwu Ke,Chao Gao,Kun Guo
Lenvatinib is a frontline tyrosine kinase inhibitor for patients with advanced hepatocellular carcinoma (HCC). However, just 25% of patients benefit from the treatment, and acquired resistance always develops. To date, there are neither effective medications to combat lenvatinib resistance nor accurate markers that might predict how well a patient would respond to the lenvatinib treatment. Thus, novel strategies to recognize and deal with lenvatinib resistance are desperately needed. In the current study, a robust Lenvatinib Resistance index (LRi) model to predict lenvatinib response status in HCC was first established. Subsequently, five candidate drugs (Mercaptopurine, AACOCF3, NU1025, Fasudil, and Exisulind) that were capable of reversing lenvatinib resistance signature were initially selected by performing the connectivity map (CMap) analysis, and fasudil finally stood out by conducting a series of cellular functional assays in vitro and xenograft mouse model. Transcriptomics revealed that the co-administration of lenvatinib and fasudil overcame lenvatinib resistance by remodeling the hedgehog signaling pathway. Mechanistically, the feedback activation of EGFR by lenvatinib led to the activation of the GLI2-ABCC1 pathway, which supported the HCC cell's survival and proliferation. Notably, co-administration of lenvatinib and fasudil significantly inhibited IHH, the upstream switch of the hedgehog pathway, to counteract GLI2 activation and finally enhance the effectiveness of lenvatinib. These findings elucidated a novel EGFR-mediated mechanism of lenvatinib resistance and provided a practical approach to overcoming drug resistance in HCC through meaningful drug repurposing strategies.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症生物学
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Revista Brasileira de Farmacognosia-Brazilian Journal of Pharmacognosy
·
2024
·Vol. 34
·期 3
·637-646
·
IF 1.4
Guo Liyang,Xue Xuexue,Zhou Yang,Chen Chunli,Sheng Zunlai
Diarrhea continues to be a major public health problem and is thought to be the cause of 525,000 child fatalities annually. Studies have shown that Macleaya cordata (Willd.) R.Br., Papaveraceae, has a good therapeutic effect on diarrhea due to its action on ion channels. However, its antidiarrheal mechanisms and key targets are not supported by scientific research. This study aimed to identify the mechanisms of action and targets of the primary active antidiarrheal compounds of M. cordata . We used network pharmacology and molecular docking to identify the antidiarrheal mechanisms and the key targets of M. cordata and its main chemical constituents. Subsequently, the experiments performed with dihydrosanguinarine (25, 50, and 100 mg/kg), which included the evaluation of the inhibitory potential of the epidermal growth factor receptor in osimertinib-induced diarrhea, real-time quantitative PCR, and western blotting, were performed for further verification of its mechanism of action. The findings revealed that of all the genes, tyrosine-protein kinase Lck, receptor tyrosine-protein kinase Erbb2, and epidermal growth factor receptor had the highest capacity of action, and the NF-kappa B and the calcium signaling pathways may play essential roles in M. cordata against diarrhea. Dihydrosanguinarine is the most active ingredient, and it significantly inhibits the increase in incidence and decreased the fecal water content of osimertinib-induced diarrhea. Western blot and qRT-PCR showed that dihydrosanguinarine works as an antidiarrheal agent by upregulating the expression of the core target epidermal growth factor receptor, affecting the NF-kappa B and the calcium ion signaling pathways, downregulating the expression of calcium-activated chloride channel and NK-kappa B P-65. Graphical
研究领域:
药理学
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分子生物学
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中药研究
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Food & Function
·
2023
·
IF 6.1
Wanying Zhong,Jian He,Wen Huang,Guangling Yin,Guo Liu,Yong Cao,Jianyin Miao
Our previous studies have shown that highly phosphorylated casein phosphopeptides (residues 1–25) P5 could efficiently bind calcium and promote intestinal calcium absorption, and enhanced bone development in rats. The purpose of this study was to investigate the effect of the phosphorylation structure in P5 on the proliferation, differentiation, and mineralization of osteoblasts (MC3T3-E1) and its mechanism. P5 was obtained by high-performance liquid chromatography (HPLC) and non-phosphorylated peptide P5-0 was obtained by chemical synthesis. Compared with the control group, the proliferation rate of MC3T3-E1 cells treated by P5 was 1.10 times that of P5-0 at 200 μg mL−1. P5 caused the cell cycle retention of MC3T3-E1 cells in the G2/M phase, while P5-0 had no significant difference in the G2/M phase. MC3T3-E1 cells incubated with P5 showed stronger alkaline phosphatase (ALP) activity than with P5-0, suggesting a tendency to promote cellular differentiation. Compared to the P5-0 treatment group, the P5 treatment group at concentrations of 10 μg mL−1 showed significant differences in the mineralization rates (p < 0.05). P5 significantly upregulated the expressions of Runx2, ALP, ColIα1, and OCN compared with the control group (p < 0.05). In addition, in silico molecular docking showed that the binding force of the P5-EGFR complex was stronger than that of the P5-0-EGFR complex, which was significantly related to the phosphorylation structure in P5 and might be an important reason for osteoblast proliferation. In conclusion, the phosphorylation structure and amino acid composition in P5 stimulated the osteogenic activity of MC3T3-E1 cells, and could be expected to be a functional food for the prevention of osteoporosis.
研究领域:
营养学
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骨骼生物学
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细胞生物学
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分子生物学
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ACS Applied Materials & Interfaces
·
2022
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IF 10.383
Xiaoxi Wang,Xueqin Zhu,Bingyu Li,Xiuyu Wei,Yalan Chen,Yun Zhang,Yan Wang,Wenyan Zhang,Sijia Liu,Zimai Liu,Wenjie Zhai,Pingping Zhu,Yanfeng Gao,Zhenzhen Chen
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, and it is associated with a high recurrence rate, metastatic potential, and poor prognosis. Thus, effective therapeutic strategies for TNBC are urgently required. The epidermal growth factor receptor (EGFR) is considered to be a potential therapeutic target for TNBC. However, there are limitations to the use of targeted therapies, such as afatinib (AFT), particularly drug resistance. Here, we investigated a poly(d,l-lactide-glycolide) (PLGA)-based intelligent bionic nanoplatform, termed AFT/2-BP@PLGA@MD, which combined targeted therapy with immunotherapy. In this platform, PLGA was used to encapsulate 2-bromo-palmitate (2-BP), a palmitoylation inhibitor, to enhance the efficacy of AFT against TNBC cells. PLGA was coated with a cancer cell membrane anchored with a cleavable peptide by matrix metalloproteinase-2 to block programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1). 2-BP significantly enhanced the capacity of AFT to inhibit the proliferation and migration of tumor cells in vitro. Moreover, the tumor cell membrane-coated AFT/2-BP@PLGA@MD nanoparticles exhibited enhanced tumor targeting ability in vivo. The AFT/2-BP@PLGA@MD nanoparticles significantly inhibited the growth and metastasis of 4T1 tumor and prolonged the survival of tumor-bearing mice. The nanoparticles also triggered antitumor immune response. Collectively, we report an effective therapeutic strategy for clinically refractory TNBC.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2026
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IF 4.9
Pei-Ling Liu,Jia-Lin Wang,Yi-Ying Dong,Hong Liu,Jin-Ju Lei,Bin Xu,Xin-Ru Liao,Di Han,Zi-Hao He,Si-Xue Cheng
Epidermal growth factor receptor (EGFR) targeted cancer therapy offers high selectivity and reduced toxicity. However, the therapeutic efficacy is compromised by the poor bioavailability of hydrophobic drugs such as gefitinib (GEF), and the acquired resistance. Curcumin (CUR) can sensitize tumor cells toward EGFR inhibitors and reverse drug resistance, but its application is also hindered by low solubility. To address these limitations, we developed a zein-based drug delivery system for the co-delivery of GEF and CUR. The dual-drug loaded zein-based nanoparticles (GEF/CUR@ZNP) decorated by pectin were prepared by self-assembly. GEF/CUR@ZNP exhibited a mean diameter less than 300 nm, featuring a narrow size distribution and an encapsulation efficiency higher than 80 %. The therapeutic efficacy was evaluated in vitro using PC-9 cells. Compared with free drugs, GEF/CUR@ZNP led to significantly enhanced cellular uptake, resulting in improved induction of cancer cell apoptosis and higher efficiency in downregulation of proteins promote cancer progression (e.g., Sp1, Bcl-2, VEGF, Snail, and CD44). To evaluate the efficacy of the drug delivery system in a context more relevant to clinical settings, we evaluated the EGFR inhibition efficacy by using the blood samples containing circulating tumor cells (CTCs) from non-small cell lung cancer (NSCLC) patients, and immunofluorescence labeling confirmed that GEF/CUR@ZNP achieved most effective suppression of EGFR expression. These findings demonstrate that zein-based co-delivery of GEF and CUR can overcome multiple barriers to targeted cancer therapy, and offer a clinically relevant strategy for enhancing antitumor efficacy and personalizing cancer treatment.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2013
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IF 3.499
Dacheng Fan,Weizhi Sun,Peiju Qiu,Zhiyong Wu,Yantuan Li,Shengbiao Wan,Tao Jiang,Lijuan Zhang
We synthesized a series of novel 3-indolyl cyclopent[ b ]indoles by trifluoroacetic acid mediated cyclodimerizations . The reaction showed high stereoselectivity and moderate to good yields. The influencing factors for stereoselectivity were systematically analyzed and a stepwise reaction mechanism was proposed. The cell viability tests in two colon and two lung cancer cell lines indicated the 1-benzyl-2-phenyl-group in 3-indolyl cyclopent[ b ]indoles was critical for the observed lower IC 50 s in these compounds. Western blot analysis demonstrated that the compound inhibited the expression and phosphorylation of EGFR through altered HSP90 expression. Further cell cycle and cell cycle check point protein analyses showed expected anti-cellular proliferation and cell cycle arresting properties associated with suppressed EGFR expression and phosphorylation. These data revealed a novel molecular mechanism explaining the observed cytotoxicities for these compounds.
研究领域:
有机化学
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药物化学
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癌症生物学
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细胞生物学
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药理学
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