Journal of Materials Chemistry B
·
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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产品关联
DOI
PubMed
高影响因子
MOLECULAR DIVERSITY
·
2024
·
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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产品关联
DOI
PubMed
高影响因子
MEDICINAL CHEMISTRY RESEARCH
·
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
Frontiers in Pharmacology
·
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
·
2025
·
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
✓ 已验证
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
·
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
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2019
·Vol. 20
·期 10
·2489
·
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
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2013
·
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
RSC Advances
·
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
✓ 已验证
DOI
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
✓ 已验证
DOI
PubMed
高影响因子
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