Journal of Materials Chemistry B
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2021
·Vol. 9
·期 22
·4577-4586
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IF 6.331
Yongjia Tang,Haoran Xu,Yaxue Dai,Fang Wang,Wenjing Huang,Peifei Liu,Yueqing Gu
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with limited diagnosis. Mesenchymal epithelial transition factor (c-Met) has become a hot target for cancer diagnosis and therapy, which is overexpressed in HCC. In this study, we labeled a novel c-Met targeting peptide YQ-M3 with a near-infrared fluorescent dye MPA and a radionuclide technetium-99m for HCC detection. YQ-M3-MPA showed high affinity for c-Met positive HepG2 tumor in vitro and higher tumor uptake and higher T/N ratio than GE137-MPA (a positive tracer for c-Met) in HepG2 tumor-bearing mice in vivo by fluorescence imaging. In addition, 99mTc-HYNIC-YQ-M3 also showed significant tumor uptake in vivo through SPECT imaging. These results indicated that c-Met positive tumors were successfully detected via fluorescence and SPECT imaging using YQ-M3-MPA and 99mTc-HYNIC-YQ-M3, respectively, and further suggested that YQ-M3-MPA and 99mTc-HYNIC-YQ-M3 have some possibly potential clinical applications for HCC diagnosis.
研究领域:
肿瘤学
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分子生物学
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医学成像
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DOI
PubMed
高影响因子
MOLECULAR DIVERSITY
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2024
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IF 3.9
Xie Tianyu,Hu Wenbo,You Lin,Wang Xin
With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3- b ] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC 50 values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581 μM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure–activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3- b ] pyridine derivatives in anti-tumor activity. Graphical abstract
研究领域:
药理学
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肿瘤学
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药物化学
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DOI
PubMed
高影响因子
MEDICINAL CHEMISTRY RESEARCH
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2015
·Vol. 24
·期 8
·3327-3333
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IF 1.402
Ye Lianbao,Wu Jie,Yang Jiebo,Chen Weiqiang,Luo Yan,Zhang Yanmei
Abstract HGF/c-Met signaling pathway has come into the spotlight as a promising therapeutic target for inhibiting tumor growth and has become one of the leading molecular targets in cancer. Various strategies are currently in development to disrupt the HGF–Met signal transduction pathway, in which small molecular inhibitors have been a particularly active field. On the basis of the structures of two c-Met inhibitors, PF-04217903 and JNJ-38877605, some novel 7-[(quinolin-6-yl)methyl] purines ( 4a – 4e ) were rationally designed on the principle of bioisosterism strategy. These compounds were synthesized and evaluated as novel c-Met inhibitors. Molecular docking experiments analyzed the results and explained the molecular mechanism of eminent activities to c-Met. The results showed that all the title compounds were active against c-Met enzyme to some extent. Though these compounds did not demonstrate inhibition as we expected, this study provided important information for building diversification of chemical library and molecular docking experiment supplied the basis for further research works. Graphical Abstract Some novel
7-[(quinolin-6-yl)methyl] purines as potential c-Met inhibitors have been designed and prepared. Their synthesis and spectral characterization are reported here.
研究领域:
癌症研究
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药物化学
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分子生物学
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产品关联
DOI
高影响因子
Genes & Genomics
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2024
·Vol. 46
·期 5
·637-646
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IF 1.6
Feng Xiu,He Shengnan,Chen Ying,Zhang Liang
Background Breast cancer type 1 susceptibility protein/breast cancer type 2 susceptibility protein-containing complex subunit 3 (BRCC3), a deubiquitinase (DUBs), is overexpressed in various cancers. However, the underlying biological roles of BRCC3 in adenocarcinoma colon (COAD) have yet to be decrypted. Objective In this work, we explored the potential biological function of BRCC3 in the natural process of COAD cells. Methods The expression levels of BRCC3 in COAD tissues and cell lines were investigated via quantitative real time polymerase chain reaction and western blotting analyses. Meanwhile, short hairpin RNAs targeting BRCC3 (sh-BRCC3) or mesenchymal-epithelial transition factor (MET) (sh-MET) were used to investigate the biological function, including proliferation, apoptosis, migration, invasion, and epithelial–mesenchymal transition (EMT) progression in COAD cells. Furthermore, the expression levels of EMT-related biomarkers were detected with western blotting analysis. Furthermore, we also performed Co-IP assay to identify the correlation between BRCC3 and MET. Results BRCC3 expression was increased in COAD tissues and cell lines. ShRNA-mediated downmodulation of BRCC3 in COAD cell lines induced EMT progression. BRCC3 knockdown resulted in decreased migration as well as invasion and increased apoptosis of SW480 and Lovo cells. Besides, MET was regulated by BRCC3 and involved in the migration, invasion, and EMT in SW480 and Lovo cells. Finally, we uncovered that the overexpressed MET reversed the effects of BRCC3 knockdown in COAD cell development. Conclusions BRCC3 acted as a critical factor in the development of COAD by deubiquitinating and stabilizing MET, which might provide an emerging biomarker for the therapeutic and diagnosis strategy of COAD.
研究领域:
肿瘤学
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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
Frontiers in Pharmacology
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2025
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IF 4.8
Jihong Bi,Yan Li,Lin Lu,Tingting Yin,Shaohua Mao,Run Zhang,Juan He,Xing Ni,Kai Wang,Jirui Bi
Objective: To investigate the protective effects of luteolin on ALI induced by lipopolysaccharide (LPS) in male mice and to explore the underlying mechanisms.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to assess the causal relationship between hepatocyte growth factor (HGF) and acute respiratory distress syndrome (ARDS). Network pharmacology analysis was employed to identify herbs that mitigate inflammation and apoptosis by upregulating HGF expression and to determine the hub active ingredients. These findings were subsequently validated through in vivo experiments using an LPS-induced ALI mouse model. Lung histopathological examination, enzyme-linked immunosorbent assay, and Western blot analysis were performed to evaluate relevant biomarkers of inflammation and apoptosis.Results: The MR analysis demonstrated a causal effect of HGF on ARDS (IVW: β = −1.120, OR = 0.326, 95% CI = 0.116–0.916, P = 0.033). Among herbs associated with upregulating HGF expression, Salvia miltiorrhiza Bunge is involved in the negative regulation of apoptotic process and positive regulation of cell population proliferation. Luteolin was identified as the hub active ingredient extracted from S. miltiorrhiza Bunge. In LPS-induced ALI mice, luteolin significantly alleviated histopatholocial damage, inflammation, and apoptosis in the lungs. However, these protective effects were abrogated by c-Met inhibition.Conclusion: Luteolin attenuates inflammation and apoptosis in the lungs of LPS-induced ALI mice via activation of the HGF/c-Met pathway.
研究领域:
免疫学
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分子生物学
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药理学
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呼吸病学
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转化医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Xingyang Qiu,Qingquan Zheng,Dongdong Luo,Yue Ming,Tingting Zhang,Wenchen Pu,Min Ai,Jianhua He,Yong Peng
Cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target for treating multiple cancers. Despite plentiful c-Met inhibitors have been developed, some issues, including the acquired drug resistance to c-Met inhibitors, have emerged to hamper their application in clinical treatment. Degradation of c-Met offers an opportunity to solve these issues. In this study, we developed a series of c-Met degraders, and the optimal compound 22b can efficiently degrade c-Met with a DC50 value of 0.59 nM in EBC-1 cells. Mechanistic studies revealed that compound 22b induced c-Met degradation via proteasome-mediated pathway. In addition, compound 22b suppressed the proliferation and also induced apoptosis of EBC-1 cells, outperforming the corresponding inhibitor tepotinib. Importantly, compound 22b showed favorable pharmacokinetic properties and significantly induced tumor regression in a xenograft model without obvious toxicity. In brief, this study provided compound 22b as a novel c-Met degrader for lung cancer therapy.
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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DOI
PubMed
高影响因子
HELVETICA CHIMICA ACTA
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2012
·Vol. 95
·期 2
·320-326
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IF 1.478
Lianbao Ye,Yuanxin Tian,Zhonghuang Li,Jiajie Zhang,Shuguang Wu
Since deregulation of the tyrosine-kinase receptor c-Met is implicated in several human cancers and is an attractive target for small-molecule-drug discovery, we report herein the synthesis of 2,3,4,5-tetrahydro-8-[1-(quinolin-6-ylmethyl)-1 H -1,2,3-triazolo[4,5- b ]pyrazin-6-yl]-1 H -pyrido[4,3- b ]indoles 4a – 4c and 2,3,4,5-tetrahydro-8-[3-(quinolin-6-ylmethyl)-1,2,4-triazolo[4,3- b ]pyridazin-6-yl]-1 H -pyrido[4,3-b]indoles 5a – 5c . These indole derivatives demonstrated inhibition of c-Met kinase activity. Concurrently, five key intermediates were synthesized. These compounds could be prepared in good yields.
研究领域:
药理学
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肿瘤学
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药物化学
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DOI
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2020
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IF 3.347
Cong Zhang,Lei Sheng,Ming Yuan,Junjie Hu,Yan Meng,Yong Wu,Liang Chen,Huifan Yu,Shan Li,Guohua Zheng,Zhenpeng Qiu
Orlistat (Xenical™), a US Food and Drug Administration (FDA)-approved anti-obesity drug, shows efficacy against multiple tumor types, including hepatocellular carcinoma (HCC), due to its ability to inhibit fatty acid synthase (FASN) activity. However, whether orlistat affects hepatocellular malignant transformation during hepatocarcinogenesis in vivo is unknown. This study assessed the antisteatotic and antitumorigenic efficacy of orlistat in a rapid HCC FVB/N mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes. Human hepatoma cell lines were used for mechanical validation in vitro . Hematoxylin and eosin staining, immunohistochemistry, and immunoblotting were applied for the mechanistic investigation. The results revealed that when orlistat was administered in the early stage of AKT/c-Met-triggered hepatocarcinogenesis, it resulted in the elimination of hepatic tumor burden. Mechanistically, orlistat efficiently elevated PTEN expression and suppressed AKT/SREBP1/FASN signaling both in vivo and in vitro , impairing AKT/c-Met-driven de novo lipogenesis and aberrant proliferation. Altogether, this study demonstrates the antilipogenic and antiproliferative efficacy of orlistat in hepatocarcinogenesis, suggesting that orlistat may be beneficial for the treatment of HCC, especially in NAFLD-related HCCs featuring activated AKT/mTOR cascade and increased lipogenesis in livers.
研究领域:
肿瘤学
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肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2025
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IF 9.6
Hui Tao,Hanhan Liu,Hanchen Zhang,Hong Ren,Binyu Wen,Jing Zhang,Jiaqi Du,Ziyi Cai,Zhihong Deng
Uveal melanoma (UM), a malignant tumor originating within the ocular, characterizes high metastasis and lethality among patients. Cancer stem cells (CSCs) distinguished by the c-Met protein are believed to mediate tumor metastasis in UM. However, the low bioavailability of c-Met inhibitors like Crizotilib (Criz) limits their clinical application. Herein, a GSH-responsive nanoparticle named NP @Oxa/Criz to precisely deliver Criz and Oxaliplatin (Oxa) is synthesized in this study. The dual-action mechanism of NP @Oxa/Criz inhibits the HGF/c-Met axis to prevent the nuclear translocation of β-Catenin, thereby reducing the transcription of metastasis-associated genes and undermining the stemness and metastasis of UM cells. Simultaneously, NP @Oxa/Criz induces immunogenic cell death to boost anti-tumor immunity. In vivo studies demonstrate that NP @Oxa/Criz can accumulate in tumor sites, significantly eradicating the primary UM in the ocular and suppressing the metastasis UM in the liver and peritoneal. The outcomes from this work illuminate the therapeutic mechanisms of NP @Oxa/Criz and provide a precise and potent nanotherapeutic strategy for clinical treatment and research in highly metastatic UM.
研究领域:
肿瘤学
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药剂学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Jinling Cui,Shuang Zhao,Hui Chen,Yuhan Fu,Kai Han,Shutao Yin,Chong Zhao,Lihong Fan,Hongbo Hu
Acquired resistance compromises the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-based therapy for non-small cell lung cancer (NSCLC), and activation of hepatocyte growth factor receptor (MET) is one of the pivotal strategies for cancer cells to acquire refractory phenotype. However, the mechanisms involved in regulating MET activity remain to be further elucidated. Using gefitinib-resistant HCC827GR cell line as a model, we unraveled that the dysregulated amino acid metabolisms reflected by elevated expression of cysteine-preferring transporter 2 (ASCT2), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) and asparagine synthetase (ASNS) might contribute to survival advantage of HCC827GR cells, and rendered the cells more sensitive to asparagine (ASN) deprivation compared to parental HCC827 cells. We further identified that the increased ASNS expression is a contributing factor for the activation of MET in HCC827GR cells. More importantly, we found that methylseleninic acid (MSeA), a precursor of methylselenol, effectively suppressed tumor growth in HCC827GR xenograft model, which is associated with decrease of intracellular ASN content along with inactivation of MET- T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling axis. Finally, we demonstrated that combination of MSeA and gefitinib induced a synergistic growth inhibition in HCC827GR cells. The findings of our work reveal that ASN-MET-TOPK signaling axis as a novel mechanism contributed to gefitinib-resistance and combined utilization of gefitinib and MSeA holds potential to improve the efficacy for gefitinib-resistant NSCLC.
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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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Mengran Xu,Fuxuan Lai,Hu Liu,Delin Hu,Yexiang Sun,Fenfen Li,Min Sun,Na Lv,Bensheng Qiu,Yueyin Pan,Yi Hu
Ferroptosis, a relatively recently discovered form of programmed cell death, has garnered considerable attention in the field of cancer drug discovery. However, effectively inducing ferroptosis at tumor sites and maximizing its therapeutic efficacy remains a formidable challenge. In the present study, we constructed the MIL-53@cMBP@ST/Ce6 (MMSC) nanocomplex to enhance the therapeutic efficacy of a ferroptosis-inducing drug. This was accomplished by modifying the cMBP peptide and encapsulating a small molecular ferroptosis inducer, sorafenib tosylate (ST), along with a photosensitizer, Chlorin e6 (Ce6), within the iron-based nanozyme MIL-53, which exhibits multiple enzyme-like activities. The glutathione (GSH) oxidase-like activity of MIL-53 depletes GSH, which is known to contribute to ferroptosis resistance in tumors. The catalase-like activity of MIL-53 catalyzes the decomposition of H 2 O 2 within the tumor, yielding oxygen to enhance the effect of photodynamic therapy. Concurrently, the photodynamic effect of MMSC generates singlet oxygen ( 1 O 2 ), further amplifying ferroptosis. Additionally, modification of the cMBP peptide enabled MMSC to attenuate the MET pathway in MET-overexpressing tumors, thereby decreasing the antioxidant capacity of these cells to promote ferroptosis. Notably, transcriptomic analysis revealed that PDT enhances the ferroptosis pathway and modulates the expression of ferroptosis-related genes and MET signaling pathways-related genes, while Western Blot results confirmed the inhibition of GPX4 protein, a critical regulator of ferroptosis. In vivo, MMSC demonstrated a tumor-specific accumulation effect, as evidenced by fluorescence imaging, and significantly inhibited tumor growth by alleviating the hypoxic tumor microenvironment and enhancing ferroptosis at the tumor site. This study presents a novel strategy for the mechanistic investigation of augmented ferroptosis in tumor therapy.
研究领域:
癌症治疗
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纳米技术
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生物化学
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分子生物学
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产品关联
DOI
高影响因子
Journal of Functional Foods
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2025
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IF 4
Ping Jiang,Yanfei He,Guangpei Xu,Chuanbo Sun
This study aims to evaluate the mechanism of RCH against CCl 4 -induced liver injury in mice. RCH treatment effectively inhibited CCl 4 -induced liver injury and apoptosis in mice, and reduced liver enzyme activities, blood inflammatory cell and serum inflammatory factor levels. Network pharmacology and machine learning predicted that PI3K-Akt pathway and Met proteins play important roles in RCH anti-CCl 4 -induced liver injury. The results of qRT-PCR and Western blot showed that RCH could down-regulate the expression of the receptor proteins Met, Tlr2, and Tlr4, and inhibit the phosphorylation of Pik3ca and Akt1, and prevent the phosphorylation of NF-κB P65, and decrease cleaved Caspase3 expression. These findings suggest that RCH effectively alleviated liver injury in CCl 4 -induced mice by inhibiting the Met/Tlr2/Tlr4-mediated PI3K-Akt signaling pathway.
研究领域:
药理学
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分子生物学
✓ 已验证
DOI
高影响因子
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