The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin rece...The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin receptor-like kinase 5, ALK5） inhibitors might have potential activity forthe treatment of relevant diseases. In this paper, the three-dimensional quantitativestructure-activity relationship （3D-QSAR） including comparative molecular field analysis （CoMFA）and comparative molecular similarity indices analysis （CoMSIA） were used to analyze thestructural requirements based on a dataset of 123 4-（[1,2,4]Triazolo[1,5-a]pyridine-6-yl）-5（3）-（6-methylpyridin-2-yl）imidazole analogues which acted as ALK5 inhibitors. The obtainedCoMFA model （q2= 0.652, r2= 0.876, r2pred = 0.845） and CoMSIA model （q^2= 0.648, r^2= 0.884,r^2pred = 0.853） were robust and satisfactory. The predictive ability of the derived models wasvalidated using a test set of 28 compounds. Additionally, potentially important structural featuresrequired to enhance activity were also elucidated by the contour maps derived from CoMFA andCoMSIA models. The results will be helpful to guide drug design strategies aimed at obtainingpotent and selective ALK5 inhibitors.展开更多
Neuroblastoma(NB),a frequently occurring pediatric disease,is derived from the neural crest cells in the sympathetic ganglia and adrenal medulla.Notably,it is a heterogeneous tumor consisting of many affection factors...Neuroblastoma(NB),a frequently occurring pediatric disease,is derived from the neural crest cells in the sympathetic ganglia and adrenal medulla.Notably,it is a heterogeneous tumor consisting of many affection factors,such as the diagnosis time within the first year and the diversity of the histology and genetic features.Despite improved outcomes in NB patients,it remains a difficult clinical problem and requires new therapeutic targets and methods.The somatic acquired activation point mutations in the receptor tyrosine kinase anaplastic lymphoma kinase(ALK)represent potential targets for treating NB.Herein,we review the underlying mechanisms of ALK in NB development,the latest available strategies to block ALK constitutive activity to treat NB,and discuss the current clinical challenges of resistance to these therapies and the strategies to overcome them.展开更多
基金supported by the Collaborative Innovation Center Project of Shanxi 'Astragalus' Resource Industrialization and Industrial Internationalization(No.HQXTCXZX2016-021)Natural Science Foundation of Shanxi Province(No.201601D011112)
文摘The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin receptor-like kinase 5, ALK5） inhibitors might have potential activity forthe treatment of relevant diseases. In this paper, the three-dimensional quantitativestructure-activity relationship （3D-QSAR） including comparative molecular field analysis （CoMFA）and comparative molecular similarity indices analysis （CoMSIA） were used to analyze thestructural requirements based on a dataset of 123 4-（[1,2,4]Triazolo[1,5-a]pyridine-6-yl）-5（3）-（6-methylpyridin-2-yl）imidazole analogues which acted as ALK5 inhibitors. The obtainedCoMFA model （q2= 0.652, r2= 0.876, r2pred = 0.845） and CoMSIA model （q^2= 0.648, r^2= 0.884,r^2pred = 0.853） were robust and satisfactory. The predictive ability of the derived models wasvalidated using a test set of 28 compounds. Additionally, potentially important structural featuresrequired to enhance activity were also elucidated by the contour maps derived from CoMFA andCoMSIA models. The results will be helpful to guide drug design strategies aimed at obtainingpotent and selective ALK5 inhibitors.
基金This work is supported by grants from the National Natural Science Foundation of China(82002633)Medical Scientific Research Foundation of Guangdong Province of China(A2019433)+1 种基金Shenzhen Health Family Planning System Research Project(SZBC2018012)to Tianfeng LiThe Science,Technology and Innovation Commission of Shenzhen(JCYJ20220531093213030)to Zhenjian Zhuo.
文摘Neuroblastoma(NB),a frequently occurring pediatric disease,is derived from the neural crest cells in the sympathetic ganglia and adrenal medulla.Notably,it is a heterogeneous tumor consisting of many affection factors,such as the diagnosis time within the first year and the diversity of the histology and genetic features.Despite improved outcomes in NB patients,it remains a difficult clinical problem and requires new therapeutic targets and methods.The somatic acquired activation point mutations in the receptor tyrosine kinase anaplastic lymphoma kinase(ALK)represent potential targets for treating NB.Herein,we review the underlying mechanisms of ALK in NB development,the latest available strategies to block ALK constitutive activity to treat NB,and discuss the current clinical challenges of resistance to these therapies and the strategies to overcome them.
