INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2019
·Vol. 20
·期 10
·2489
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IF 4.183
Siqi Zhang,Qiaoling Song,Xueting Wang,Zhiqiang Wei,Rilei Yu,Xin Wang,Tao Jiang
c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including7a,7b,8a,8band12c(with IC50values of less than 20 μM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.Keywords:virtual screening;benzoisoselenone;c-Met inhibition;docking;molecular dynamics simulation
研究领域:
药理学
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分子生物学
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癌症研究
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药物化学
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DOI
PubMed
高影响因子
ONCOLOGY RESEARCH
·
2026
·Vol. 34
·期 10
·21
·
IF 4.6
Zhiyi Min,Chunbin Wang,Tongjin Yin,Wanyan Jiao,Dandan Zhou,Xuyao Zhang,Junli Cui,Zhe Ding
Objectives: MET inhibitors have demonstrated clinical efficacy in several MET-driven malignancies; however, their therapeutic potential in pancreatic cancer remains insufficiently characterized. This study aimed to evaluate the antitumor activity of the selective MET inhibitor savolitinib in MET-high pancreatic cancer and to investigate the role of autophagy in the cellular response to MET inhibition. Methods: MET-high pancreatic cancer cell lines (AsPC-1 and BxPC-3) were treated with savolitinib. Cell viability, apoptosis, transcriptomic profiling, and signaling pathway analyses were performed to characterize its antitumor effects and underlying mechanisms. Autophagy induction was assessed using monodansylcadaverine (MDC) staining, transmission electron microscopy, lysosomal co-localization analysis, and western blotting of autophagy-related markers. The therapeutic efficacy of combining savolitinib with the autophagy inhibitor chloroquine was further evaluated in vitro and in BxPC-3 xenograft models. Results: Savolitinib significantly inhibited MET phosphorylation and reduced the viability of MET-high pancreatic cancer cells while inducing apoptosis, as evidenced by increased levels of cleaved PARP, cleaved caspase-3, and an elevated Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) ratio. Transcriptomic analysis revealed significant enrichment of autophagy-related pathways among savolitinib-responsive genes. Savolitinib induced autophagy-associated vesicular changes and autophagic flux, accompanied by suppression of AKT/mTOR signaling. Pharmacological inhibition of autophagy with chloroquine markedly enhanced savolitinib-induced apoptosis in vitro and significantly improved tumor growth inhibition in vivo , achieving a tumor growth inhibition rate of 84.96% in the combination-treatment group without obvious systemic toxicity under the tested conditions. Conclusion: Savolitinib-induced autophagy functions as an adaptive cytoprotective response in MET-high pancreatic cancer. Combined inhibition of MET and autophagy enhances antitumor activity and warrants further evaluation in MET-high pancreatic cancer models.
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2013
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IF 3.499
Lianbao Ye,Xiaomin Ou,Yuanxin Tian,Bangwei Yu,Yan Luo,Binghong Feng,Hansen Lin,Jiajie Zhang,Shuguang Wu
Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is considered as an attractive target for small molecule drug discovery . In this study, a series of indazoles were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibition on c-Met and compound 4d showed highest activity against c-Met with IC 50 value of 0.17 μM in TR-FRET-based assay and IC 50 value of 5.45 μM in cell-based assay as compared to other tested compounds. Molecular docking experiments verified the results and explained the molecular mechanism of pretty activities to c-Met.
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产品关联
DOI
PubMed
高影响因子
Materials
·
2023
·Vol. 16
·期 2
·638
·
IF 3.4
Wanli Zhou,Haohua Ma,Yunqiao Dai,Yijing Du,Cheng Guo,Jianqiang Wang
A nanoantioxidant of mesoporous organosilica (Trp-Met-PMO) based on the framework of tryptophan–methionine dipeptide was first designed and constructed by condensation between self-created dipeptide organosilica precursor (Trp-Met-Si) and tetraethyl orthosilicate (TEOS) in alkaline conditions under the template hexadecyl trimethyl ammonium bromide (CTAB). Trp-Met-Si was prepared by the reaction between dipeptide Trp-Met and conventional organosilicon coupling agent isocyanatopropyltriethoxysilane (IPTES) via a multiple-step reaction method. The material Trp-Met-PMO was confirmed by XRD, FT-IR and N2adsorption–desorption analysis. The material Trp-Met-5-PMO with low amounts of organosilica precursor remained a mesoporous material with well-ordered 2D hexagonal (P6mm) structure. With increasing amounts of organosilica precursor, a mesoporous structure was still formed, as shown in the material Trp-Met-100-PMO with the highest amounts of organosilica precursor. Moreover, pore size distribution, surface area and porosity of Trp-Met-PMO are regulated with different amounts of organosilica precursor Trp-Met-Si. The antioxidant activity of Trp-Met-PMO was evaluated by ABTS free radical-scavenging assay. The results showed that antioxidant activity was largely enhanced with increasing contents of organosilica precusor Trp-Met-Si in the skeleton. The material Trp-Met-40-PMO exhibited maximum scavenging capacity of ABTS free radicals, the inhibition percent was 5.88%. This study provides a design strategy for nanoantioxidant by immobilizing short peptides within the porous framework of mesoporous material.Keywords:mesoporous organosilica;ROS;nanoantioxidant;tryptophan–methionine;dipeptide framework
研究领域:
材料科学
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生物化学
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产品关联
DOI
PubMed
高影响因子
TALANTA
·
2023
·
IF 6.1
Zhilan Zhou,Ya Wang,Zhengtao Shao,Guixi Zhang,Hang Jiang,Yiyuan Tang,Zening Huang,Yingdi Zhu,Juan Li
Drug resistance is a worldwide health care crisis which impedes disease treatment and increases financial burden, especially for its multifactorial nature and high complexity. Herein, we developed a multiparametric approach to visualize and detect drug resistance in living cancer cells, through the combination of DNA-templated covalent protein labeling strategy and fluorescent resonance energy transfer technique. Gefitinib resistance in non-small cell lung cancer caused by mesenchymal-epidermal transition factor (Met) overexpression and hyperactivation was investigated as a proof-of-concept. Unlike the traditional single-factor investigation, the proposed approach evaluated the contribution of three important parameters towards the resistance, including the changes of Met expression level, the homodimerization of Met with itself and the heterodimerization of Met with epidermal growth factor receptor (EGFR). A multiple regression model based on these three parameters was tentatively established for evaluation of the resistance level of laboratory-developed resistant cells and evaluation of the resistance level of patient-derived cells. Such an approach facilitates a quick identification of a drug resistance, to evaluate not only the resistance level but also the resistance mechanism.
研究领域:
癌症生物学
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分子生物学
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药理学
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细胞生物学
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生物医学工程
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DOI
PubMed
高影响因子
RSC Advances
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2017
·Vol. 7
·期 7
·3760-3767
·
IF 3.108
Lianbao Ye,Jie Wu,Weiqiang Chen,Yu Feng,Zhibing Shen
Germacrone is a major activity component found in Curcuma zedoaria oil product, which is extracted from Curcuma zedoaria. In the present study, novel germacrone derivatives were first designed based on the theories of bioalkylating agents, synthesized, and then investigated for their inhibition effects on Bel-7402, HepG2, A549, and HeLa cells. Moreover, the study also evaluated the inhibition of these derivatives on c-Met kinase, which is expressed in a number of cancers. The results indicated that most of the compounds showed a stronger inhibitory effect on cancer cells and c-Met kinase than germacrone. Besides these findings, molecular docking studies were also carried out to analyze the results and explain the molecular mechanism of activities to c-Met kinase. Molecular dynamics simulations have been carried out for the further evaluation of binding stabilities between the compounds and their receptors.
研究领域:
药理学
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肿瘤学
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计算生物学
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DOI
高影响因子
Frontiers in Cell and Developmental Biology
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2026
·
IF 5.3
Gongyu Wu,Huilin Guan,Mengyao Lv,Zhiqiang Chen,Changjiu Gao,Wanzhen Su,Hui Fu
Background 18β-Glycyrrhetinic acid (18β-GA), a major bioactive triterpenoid from licorice, has demonstrated anti-cancer potential; however, its mechanisms against lung adenocarcinoma (LUAD) remain unclear. Methods This study employed an integrated approach combining network pharmacology, bioinformatics, and experimental validation to investigate the anti-LUAD efficacy and underlying molecular targets of 18β-GA. Results In vitro and in vivo assays demonstrated that 18β-GA dose-dependently inhibited LUAD cell proliferation, migration, and colony formation, while significantly suppressing tumor growth in a Lewis lung carcinoma (LLC) allograft model. By integrating network pharmacology with TCGA transcriptomic data, MET was identified as a core upstream target, and the PI3K/AKT signaling pathway was revealed as a significantly enriched pathway. Molecular docking and molecular dynamics simulations revealed that 18β-GA forms stable, high-affinity complexes in the catalytic pockets of both MET and AKT. Subsequent biological validations confirmed that 18β-GA attenuated the phosphorylation of critical signaling components, including MET, PI3K, AKT, and mTOR, without altering their mRNA or total protein expression. Crucially, functional rescue assays revealed that exogenous MET activation via its specific ligand HGF simultaneously reversed the 18β-GA-induced suppression of both p-MET and p-AKT. In contrast, the AKT agonist SC79 effectively restored p-AKT levels and reversed the anti-tumor efficacy of 18β-GA, but it failed to rescue the inhibition of upstream p-MET. This unidirectional reversal rigorously validates MET as the upstream regulator of AKT. Conclusion 18β-GA suppresses LUAD by targeting upstream MET to drive a top-down cascade blockade of the PI3K/AKT/mTOR signaling pathway, providing a pharmacological rationale for its application in LUAD targeted therapy.
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DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
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2024
·
IF 4.3
Haoyu Wang,Haitian Jiang,Yining Tao,Binghui Yang,Jiakang Shen,Haoran Mu,Chongren Wang,Xiyu Yang,Zhengdong Cai,Mu Li,Wei Sun,Liu Yang,Mengxiong Sun
Introduction: Osteosarcoma, characterized by high mortality and disability rates, poses a significant challenge due to its complex genetic background and the absence of specific membrane receptors, which hinder effective targeted therapy. Active targeting has emerged as a promising approach to address this issue.Methods: In this study, magnetically driven hydrogel robots (MMHR) were utilized to load and deliver drugs precisely to target sites. The drugs included SCR1481B16, a specific MET inhibitor proven to inhibit MET-driven tumor growth, and Anlotinib. The microrobots were designed to navigate under magnetic guidance, enhancing drug efficacy while minimizing damage to normal tissues.Results: The study explored the potential of MMHR loaded with SCR1481B16 and Anlotinib in the treatment of Anlotinib-resistant osteosarcoma. The microrobots were successfully designed and produced, demonstrating the ability to deliver drugs precisely to tumor sites. Evaluation of the microrobots showed an enhanced sensitivity of tumors to Anlotinib, providing new insights into the treatment of drug-resistant osteosarcoma.Discussion: Tumors overexpressing MET often develop resistance to VEGFR-targeted drugs. The use of SCR1481B16 as a MET inhibitor in combination with Anlotinib, delivered by magnetically driven hydrogel microrobots, offers a novel strategy to overcome this resistance. However, further in-depth research and validation are required before the clinical application of this method can be considered.Conclusion: In conclusion, magnetically driven hydrogel microrobots loaded with SCR1481B16 provide a promising new strategy for enhancing the sensitivity of Anlotinib-resistant osteosarcoma, bringing hope for future clinical applications in the treatment of this challenging disease.
研究领域:
肿瘤学
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生物医学工程
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药理学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Han Zhang,Shuqing Chen,Guodong Zhang,Yongbin Wang,Zichen Cui,Fei Chen,Yukun Du,Guanghui Gu,Tianyu Bai,Changlin Lv,Wenkang Yang,Shiqi Xu,Jianwei Guo,Weiqing Kong,Yongming Xi
Addressing the clinical challenge of spatiotemporal coordination between vascularization and osteogenesis in bone repair, this study develops a composite scaffold system integrating piezoelectric stimulation and controlled drug release to achieve sequential regulation of angiogenesis-osteogenesis coupling. Combining piezoelectric barium titanate/nano-hydroxyapatite/polycaprolactone (BTO/nHA/PCL, BHP) with metformin (Met)-loaded GelMA (G@Met) hydrogels, the BHP/G@Met scaffolds are fabricated through dual-nozzle 3D printing. Material characterization confirms hierarchical porosity, stable piezoelectric output under ultrasound (US), and sustained drug release kinetics aligned with early-phase vascularization requirements. In vitro co-culture models demonstrate enhanced endothelial cell migration and tubular network formation during the initial 7d phase, followed by potent osteogenic differentiation of mesenchymal stem cells at intermediate (14d) and terminal (21d) periods. Dual-animal models reveal superior bone regeneration with extensive neovascularization and osseous tissue infiltration. Transcriptome sequencing and network pharmacological analyses identify PI3K-AKT signaling as the central pathway for BHP/G@Met coordinating sequential angiogenesis-osteogenesis. By synergizing piezoelectric bioelectrical cues with spatiotemporal drug delivery, BHP/G@Met pioneers a chronologically adaptive strategy to match the spatial-temporal bone healing microenvironments, offering a paradigm for dynamic tissue regeneration.
研究领域:
生物材料
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组织工程
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再生医学
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生物医学工程
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纳米技术
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药理学
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细胞生物学
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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
·
IF 5.3
Liang Fang,Junying Li,Hongyan Cheng,Huanhuan Liu,Caiyun Zhang
Borneol is an aromatic traditional Chinese medicine that can improve the permeability of the blood–brain barrier (BBB), enter the brain, and promote the brain tissue distribution of many other drugs. In our previous study, borneol-metformin hydrochloride water/oil/water composite submicron emulsion (B-Met-W/O/W SE) was prepared using borneol and SE to promote BBB penetration, which significantly increased the brain distribution of Met. However, the dynamic images, transport pathway (uptake and efflux), promotion of BBB permeability, and mechanisms of B-Met-W/O/W SE before and after entering cells have not been clarified. In this study, rhodamine B and coumarin-6 were selected as water-soluble and oil-soluble fluorescent probes to prepare B-Met-W/O/W dual-fluorescent SE (B-Met-W/O/W DFSE) with concentric circle imaging. B-Met-W/O/W SE can be well taken up by brain microvascular endothelial cells (BMECs). The addition of three inhibitors (chlorpromazine hydrochloride, methyl-β-cyclodextrin, and amiloride hydrochloride) indicated that its main pathway may be clathrin-mediated and fossa protein-mediated endocytosis. Meanwhile, B-Met-W/O/W SE was obviously shown to inhibit the efflux of BMECs. Next, BMECs were cultured in the Transwell chamber to establish a BBB model, and Western blot was employed to detect the protein expressions of Occludin, Zona Occludens 1 (ZO-1), and p-glycoprotein (P-gp) after B-Met-W/O/W SE treatment. The results showed that B-Met-W/O/W SE significantly down-regulated the expression of Occludin, ZO-1, and P-gp, which increased the permeability of BBB, promoted drug entry into the brain through BBB, and inhibited BBB efflux. Furthermore, 11 differentially expressed genes (DEGs) and 7 related signaling pathways in BMECs treated with B-W/O/W SE were detected by transcriptome sequencing and verified by quantitative real-time polymerase chain reaction (qRT-PCR). These results provide a scientific experimental basis for the dynamic monitoring, transmembrane transport mode, and permeation-promoting mechanism of B-Met-W/O/W SE as a new brain-targeting drug delivery system.
研究领域:
药剂学
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神经科学
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药物递送系统
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生物药剂学
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分子生物学
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DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Jie Wu,Yu Feng,Chao Han,Wu Huang,Zhibin Shen,Mengdie Yang,Weiqiang Chen,Lianbao Ye
Germacrone is one of the major bioactive components in the Curcuma zedoaria oil product, which is extracted from Curcuma zedoaria Roscoe, known as zedoary . The present study designed some novel germacrone derivatives based on combination principles, synthesized these compounds, and investigated their inhibitions on Bel-7402, HepG2, A549 and HeLa cells. Meanwhile, the study evaluated inhibitions of these derivatives on c-Met kinase, which has been detected in a number of cancers. The results suggested that the majority of the compounds showed stronger inhibitory effect on cancers and c-Met kinase than germacrone. Furthermore, our docking experiments analyzed the results and explained the molecular mechanism. Molecular dynamics simulations were then applied to perform further evaluation of the binding stabilities between compounds and their receptors.
研究领域:
药理学
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有机化学
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计算生物学
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DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2024
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IF 8
Luting Yan,Yuhao Zhang,Qi Guo,Lei Tian,Falan Li,Qingqing Yang,Yanyan Zhang
Most electrochemiluminescent (ECL) biosensors currently necessitate coreactants that affect sensor detection accuracy and increase sensor construction complexity. This study detailed the creation of an ECL biosensor without coreactant, utilizing Methionine-capped Au nanoclusters (Met-AuNCs) as luminophore and a Pb 2+ -dependent DNAzyme-mediated DNA walker signal amplification strategy to detect Vibrio parahaemolyticus (Vp) in scallops. Double-stranded DNA (dsDNA) was produced through hybridization of the Vp aptamer with DNA walker. The electrode surface was loaded with cDNA labeled with Met-AuNCs. Upon the presence of Vp, it competitively bound to the aptamer, resulting in dsDNA dissociation and exposing the DNAzyme sequence in the DNA walker. The introduction of Pb 2+ initiated the activation and circulation of the DNAzyme-mediated DNA walker on the electrode surface, causing the cDNA to be sheared. As a result, the cDNA-Met-AuNCs on the surface of the electrode decreased, resulting in a reduction of ECL signal intensity. The ECL biosensor detected Vp at a range of 1.00×10 1 -1.00×10 7 CFU/mL, under optimal conditions, with the limit of detection (LOD) being 1.23 CFU/mL. In this work, the biosensor demonstrated excellent stability and specificity and had proven successful in detecting actual samples of aquatic products. This study offers a novel ECL method without a coreactant for the detection of foodborne pathogens in aquatic products.
研究领域:
生物化学
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纳米技术
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食品安全
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分析化学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）