摘要
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.
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)
作者简介
Corresponding author:Xiaoxin Chen,Tel.:+8676981388217,fax:+8676986188080-27,E-mail addresses:chenzhenyu2000@zspcl.com;Corresponding author:Jinliang Yang,Tel.:+862885501580,fax:+862885501580,E-mail addresses:jlyang01@163.com
