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.
10.1016/j.apsb.2020.04.002
- Author:
Yuqin YAO
1
;
Zhuowei LIU
1
;
Manyu ZHAO
1
;
Zhengxia CHEN
2
;
Peng LI
2
;
Yang ZHANG
2
;
Yuxi WANG
1
;
Chengjian ZHAO
1
;
Chaofeng LONG
3
;
Xiaoxin CHEN
3
;
Jinliang YANG
1
Author Information
1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
2. WuXi AppTec Ltd. Shanghai 200131, China.
3. Guangdong Zhongsheng Pharmaceutical Co., Ltd., Dongguan 523325, China.
- Publication Type:Journal Article
- 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
- From:
Acta Pharmaceutica Sinica B
2020;10(8):1453-1475
- CountryChina
- Language:English
-
Abstract:
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/PDGFR simultaneously . 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.
