Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold...Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC_(50))of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal“dead ends”and“safe bets”for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogeneoxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.展开更多
目的观察黄芪建中汤对脾胃虚寒证胃溃疡大鼠炎症因子及HGF/c-Met信号通路的影响。方法将60只大鼠随机分为4组,即正常组、模型组、黄芪建中汤组[黄芪建中汤6.8 g/(kg·d)]、奥美拉唑组[奥美拉唑肠溶胶囊4.2 mg/(kg·d)],每组15...目的观察黄芪建中汤对脾胃虚寒证胃溃疡大鼠炎症因子及HGF/c-Met信号通路的影响。方法将60只大鼠随机分为4组,即正常组、模型组、黄芪建中汤组[黄芪建中汤6.8 g/(kg·d)]、奥美拉唑组[奥美拉唑肠溶胶囊4.2 mg/(kg·d)],每组15只大鼠。正常组除外,其他组采用耗气破气法结合饥饱失常法进行大鼠脾胃虚寒证模型造模,再采用冰醋酸法建立大鼠胃溃疡模型。比较各组大鼠体质量、溃疡指数;HE染色观察大鼠胃组织病理学变化;采用酶联免疫吸附法检测血清中白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)含量;免疫组化法检测胃组织中肝细胞生长因子(HGF)、肝细胞生长因子受体(c-Met)表达;荧光定量PCR检测胃组织HGF、c-Met m RNA水平。结果与正常组相比,模型组大鼠体质量降低,溃疡指数升高,IL-6、IL-1β、TNF-α含量升高,HGF升高,HGF、c-Met m RNA升高(P<0.05);与模型组相比,黄芪建中汤组和奥美拉唑组大鼠体质量升高,溃疡指数降低,IL-6、IL-1β、TNF-α降低,HGF升高,HGF、c-Met mRNA升高(P<0.05)。结论黄芪建中汤可以通过抑制炎症因子、调节HGF/c-Met通路的表达促进胃黏膜修复。展开更多
Hepatocyte growth factor(HGF)and its receptor,c-Met,play important roles in the occurrence,development,and treatment of gastric cancer(GC).This review explored the function of the HGF/c-Met signaling pathway in GC and...Hepatocyte growth factor(HGF)and its receptor,c-Met,play important roles in the occurrence,development,and treatment of gastric cancer(GC).This review explored the function of the HGF/c-Met signaling pathway in GC and its potential targeted therapeutic mechanisms.As one of the most common malignant tumors worldwide,GC has a complex pathogenesis and limited therapeutic options.Therefore,a thorough understanding of the molecular mechanism of GC is very important for the development of new therapeutic methods.The HGF/c-Met signaling pathway plays an important role in the proliferation,migration,and invasion of GC cells and has become a new therapeutic target.This review summarizes the current research progress on the role of HGF/c-Met in GC and discusses targeted therapeutic strategies targeting this signaling pathway,providing new ideas and directions for the treatment of GC.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:82173699 and 32200531)Shanghai Jiao Tong University Trans-Med Awards Research,China(STAR Project No.:20230101)Shanghai Science and Technol-ogy Commission,China(Grant No.:23DZ2290600).
文摘Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC_(50))of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal“dead ends”and“safe bets”for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogeneoxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.
基金supported by the National Natural Science Foundation of China(No.81472656)Anhui Provincial Natural Science Foundation(No.2022AH040224)+2 种基金Anhui Provincial Natural Science Foundation(No.2023AH051991)Key Research Project at the School Level of Bengbu Medical College(No.Byycx23084)Bengbu Medical College National College Students'Innovation and Entrepreneurship Training Program Project(No.202310367011).
文摘目的观察黄芪建中汤对脾胃虚寒证胃溃疡大鼠炎症因子及HGF/c-Met信号通路的影响。方法将60只大鼠随机分为4组,即正常组、模型组、黄芪建中汤组[黄芪建中汤6.8 g/(kg·d)]、奥美拉唑组[奥美拉唑肠溶胶囊4.2 mg/(kg·d)],每组15只大鼠。正常组除外,其他组采用耗气破气法结合饥饱失常法进行大鼠脾胃虚寒证模型造模,再采用冰醋酸法建立大鼠胃溃疡模型。比较各组大鼠体质量、溃疡指数;HE染色观察大鼠胃组织病理学变化;采用酶联免疫吸附法检测血清中白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)含量;免疫组化法检测胃组织中肝细胞生长因子(HGF)、肝细胞生长因子受体(c-Met)表达;荧光定量PCR检测胃组织HGF、c-Met m RNA水平。结果与正常组相比,模型组大鼠体质量降低,溃疡指数升高,IL-6、IL-1β、TNF-α含量升高,HGF升高,HGF、c-Met m RNA升高(P<0.05);与模型组相比,黄芪建中汤组和奥美拉唑组大鼠体质量升高,溃疡指数降低,IL-6、IL-1β、TNF-α降低,HGF升高,HGF、c-Met mRNA升高(P<0.05)。结论黄芪建中汤可以通过抑制炎症因子、调节HGF/c-Met通路的表达促进胃黏膜修复。
文摘Hepatocyte growth factor(HGF)and its receptor,c-Met,play important roles in the occurrence,development,and treatment of gastric cancer(GC).This review explored the function of the HGF/c-Met signaling pathway in GC and its potential targeted therapeutic mechanisms.As one of the most common malignant tumors worldwide,GC has a complex pathogenesis and limited therapeutic options.Therefore,a thorough understanding of the molecular mechanism of GC is very important for the development of new therapeutic methods.The HGF/c-Met signaling pathway plays an important role in the proliferation,migration,and invasion of GC cells and has become a new therapeutic target.This review summarizes the current research progress on the role of HGF/c-Met in GC and discusses targeted therapeutic strategies targeting this signaling pathway,providing new ideas and directions for the treatment of GC.
