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

作     者：Yuqin Yao Zhuowei Liu Manyu Zhao Zhengxia Chen Peng Li Yang Zhang Yuxi Wang Chengjian Zhao Chaofeng Long Xiaoxin Chen Jinliang Yang Yuqin Yao;Zhuowei Liu;Manyu Zhao;Zhengxia Chen;Peng Li;Yang Zhang;Yuxi Wang;Chengjian Zhao;Chaofeng Long;Xiaoxin Chen;Jinliang Yang

作者机构：State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China School of Public Health and West China Fourth HospitalSichuan UniversityChengdu 610041China Guangdong Zhongsheng Pharmaceutical Co.Ltd.Dongguan 523325China West China School of Public Health and West China Fourth HospitalHealthy Food Evaluation Research CenterSichuan UniversityChengdu 610041China Guangdong Raynovent Biotech Co.Ltd.Dongguan 523325China WuXi AppTec Ltd.Shanghai 200131China 

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) 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2020年第10卷第8期

页      码：1453-1475页

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 *** 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.

主 题 词：inhibited clinical synthesis 

学科分类：1007[医学-药学类] 1006[医学-中西医结合类] 100706[100706] 100701[100701] 100602[100602] 10[医学] 

核心收录：

D　O　I：10.1016/j.apsb.2020.04.002

馆 藏 号：203969559...