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.

血管激酶，例如血管内皮、成纤维细胞和血小板衍生的生长因子受体（VEGFR、FGFR 和 PDGFR）在肿瘤血管生成中发挥着至关重要的作用。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成功。在本研究中，我们介绍了新型三联血管激酶抑制剂WXFL-152的设计、合成、靶点识别、分子机制、药效学（PD）和药代动力学（PK）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出来的，通过阻断血管激酶信号 VEGF/VEGFR2、FGF/FGFR 和 PDGF/PDGFR 来抑制血管内皮细胞 (EC) 和周细胞的增殖β同时体外。 WXFL-152 的显着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，大鼠和比格犬口服单剂量和连续多剂量具有良好的生物利用度。综上所述，目前处于Ib期临床试验的WXFL-152是一种新型有效的三重血管激酶抑制剂，在肿瘤治疗中具有明确的PD和PK。