Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response.Multiple organs can develop fibrosis,including the liver,kidney,heart,and lung...Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response.Multiple organs can develop fibrosis,including the liver,kidney,heart,and lung.Fibrosis such as liver cirrhosis,idiopathic pulmonary fibrosis,and cystic fibrosis caused substantial disease burden.Persistent abnormal activation of myofibroblasts mediated by various signals,such as transforming growth factor,platelet-derived growth factor,and fibroblast growh factor,has been recongized as a major event in the occurrence and progression of fibrosis.Although the mechanisms driving organ-specific fibrosis have not been fully elucidated,drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials.In this review,we briefly introduce the aetiology and epidemiology of several fibrosis diseases,including liver fibrosis,kidney fibrosis,cardiac fibrosis,and pulmonary fibrosis.Then,we summarise the abnormal cells(epithelial cells,endothelial cells,immune cells,and fibroblasts)and their interactions in fibrosis.In addition,we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation,extracellular matrix cross-linking,metabolism,and inflammation in fibrosis.Finally,we discuss the anti-fibrotic drugs based on their targets and clinical trials.This review provides reference for further research on fibrosis mechanism,drug development,and clinical trials.展开更多
Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinas...Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics(PD)and pharmacokinetics(PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152,identified from a series of 4-oxyquinoline derivatives based on a structureeactivity relationship study,inhibited the proliferation of vascular endothelial cells(ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patientderived tumor xenograft(PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles.In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective tripleangiokinase inhibitor with clear PD and PK in tumor therapy.展开更多
基金supported by the National Science Foundation of China(No.81773375)the National Major Scientific and Technological Special Project(No.2019ZX09201001)。
文摘Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response.Multiple organs can develop fibrosis,including the liver,kidney,heart,and lung.Fibrosis such as liver cirrhosis,idiopathic pulmonary fibrosis,and cystic fibrosis caused substantial disease burden.Persistent abnormal activation of myofibroblasts mediated by various signals,such as transforming growth factor,platelet-derived growth factor,and fibroblast growh factor,has been recongized as a major event in the occurrence and progression of fibrosis.Although the mechanisms driving organ-specific fibrosis have not been fully elucidated,drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials.In this review,we briefly introduce the aetiology and epidemiology of several fibrosis diseases,including liver fibrosis,kidney fibrosis,cardiac fibrosis,and pulmonary fibrosis.Then,we summarise the abnormal cells(epithelial cells,endothelial cells,immune cells,and fibroblasts)and their interactions in fibrosis.In addition,we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation,extracellular matrix cross-linking,metabolism,and inflammation in fibrosis.Finally,we discuss the anti-fibrotic drugs based on their targets and clinical trials.This review provides reference for further research on fibrosis mechanism,drug development,and clinical trials.
基金supported by the National Major Scientific and Technological Special Project(Nos.2018ZX09201002,2018ZX09711001-011 and 2019ZX09201001)the National Natural Science Foundation of China(No.81773375)
文摘Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics(PD)and pharmacokinetics(PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152,identified from a series of 4-oxyquinoline derivatives based on a structureeactivity relationship study,inhibited the proliferation of vascular endothelial cells(ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patientderived tumor xenograft(PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles.In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective tripleangiokinase inhibitor with clear PD and PK in tumor therapy.
