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
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
复制标题
4-(3-氯-4-(3-环丙基硫脲基)-2-氟苯氧基)-7-甲氧基喹啉-6-甲酰胺(WXFL-152)的设计、合成和药理学评价：一种用于癌症治疗的新型三重血管激酶抑制剂
DOI：
10.1016/j.apsb.2020.04.002
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发表时间：
2020-08-01
影响因子：
14.5
通讯作者：
Yang, Jinliang
中科院分区：
文献类型：
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作者：
Yao, Yuqin;Liu, Zhuowei;Yang, Jinliang
血管激酶，如血管内皮、成纤维细胞和血小板衍生生长因子受体（VEGF、FGFR和PDGFR）在肿瘤血管生成中起关键作用。近年来，使用多种血管激酶抑制剂的抗血管生成治疗取得了巨大的成功。本论文对新型三联血管激酶抑制剂WXFL-152的设计、合成、靶点鉴定、分子机制、药效学和药代动力学进行了研究。WXFL-152是基于构效关系研究从一系列4-羟基喹啉衍生物中鉴定的，其通过同时阻断血管激酶信号VEGF/VEGFR 2、FGF/FGFRs和PDGF/PDGFR β来抑制血管内皮细胞（EC）和周细胞的增殖。WXFL-152的显著抗癌作用在多个临床前肿瘤异种移植模型中得到证实，包括患者来源的肿瘤异种移植（PDX）模型。WXFL-152的药代动力学研究表明，大鼠和比格犬单次给药和连续多次给药具有良好的生物利用度。总之，目前处于Ib期临床试验的WXFL-152是一种新型有效的三联血管激酶抑制剂，在肿瘤治疗中具有明确的PD和PK。(C)2020中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
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 beta 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. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.