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 structure-activity 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 patient-derived 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 triple-angiokinase inhibitor with clear PD and PK in tumor therapy.
Keywords: ATCC, American Type Culture Collection; AUC, area under the plasma concentration–time curve; Anti-angiogenesis therapy; CE, collision energy; CL, systemic clearance; Cmax, maximum plasma concentration; Drug synthesis; EC, vascular endothelial cell; ECM, endothelial cell medium; ERKs, extracellular signal-regulated kinases; FGF, fibroblast growth factor; FGFRs, fibroblast growth factor receptors; HBVPs, human brain vascular pericytes; HUVECs, human umbilical vein endothelial cells; IC50, half maximal inhibitory concentration; IHC, immunohistochemistry; LC–MS, liquid chromatography mass spectrometry; LLOQ, lower limit of quantification; MRM, multiple reaction monitoring; MsOH, methane sulfonic acid; Multi-angiokinase inhibitor; NMR, nuclear magnetic resonance; PD, pharmacodynamics; PDB, protein data bank; PDGF, platelet-derived growth factor; PDGFRs, platelet-derived growth factor receptors; PDX, patient-derived tumor xenograft; PK, pharmacokinetics; PM, pericyte medium; Pharmacokinetic; QC, quality control; RE, values and relative error; RSD, relative standard deviation; RTKs, receptor tyrosine kinases; TGI, tumor growth inhibition rate; TLC, thin-layer chromatography; Tmax, time the maximum concentration occurred; Tumor; ULOQ, up limit of quantitation; VEGF, vascular endothelial growth factor; VEGFRs, vascular endothelial growth factor receptors; Vdss, volume of distribution at steady state; i.v., intravenous injection; p.o., per os.
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