Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152):a novel triple angiokinase inhibitor for cancer therapy

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.

ETV2 mediates endothelial transdifferentiation of glioblastoma

Glioblastoma multiforme(GBM)is characterized by extensive endothelial hyperplasia.Recent studies suggest that a subpopulation of endothelial cells originates via vasculogenesis by the transdifferentiation of GBM tumor cells into endothelial cells(endotransdifferentiation).The molecular mechanism underlying this process remains poorly defined.Here,we show that the expression of ETS variant 2(ETV2),a master regulator of endothelial cell development,is highly correlated with malignancy.Functional studies demonstrate that ETV2 is sufficient and necessary for the transdifferentiation of a subpopulation of CD133+/Nestin+GBM/neural stem cells to an endothelial lineage.Combinational studies of ChIP-Seq with gain-of-function RNA-Seq data sets suggest that ETV2,in addition to activating vascular genes,represses proneural genes to direct endo-transdifferentiation.Since endotransdifferentiation by ETV2 is VEGF-A independent,it likely accounts for the observed resistance of GBM tumor cells to antiangiogenesis therapy.Further characterization of the regulatory networks mediated by ETV2 in endo-transdifferentiation of GBM tumor cells should lead to the identification of more effective therapeutic targets for GBM.