Discovery, Synthesis, and Evaluation of Highly Selective Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Inhibitor for the Potential Treatment of Metastatic Triple-Negative Breast Cancer
Discovery, Synthesis, and Evaluation of Highly Selective Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Inhibitor for the Potential Treatment of Metastatic Triple-Negative Breast Cancer
复制标题
用于治疗转移性三阴性乳腺癌的高选择性血管内皮生长因子受体 3 (VEGFR3) 抑制剂的发现、合成和评估
DOI：
10.1021/acs.jmedchem.1c00678
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发表时间：
2021-08-05
影响因子：
7.3
通讯作者：
Ouyang, Liang
中科院分区：
文献类型：
--
作者：
Li, Yang;Yang, Gaoxia;Ouyang, Liang
本文报道了一种新型的选择性血管内皮生长因子受体3(VEGFR3)抑制剂--硫代并[2，3-d]嘧啶类化合物的鉴定、结构优化及其构效关系。在已开发的化合物中，N-(4-Chloro-3-(trifluoromethyl)phenyl)-4-(6-(4-(4-methylpiperazin-1-yl)phenyl)thieno[2，3-d]pyrimidin-4-yl)piperazine-1-carboxamide(38K)是最有效的VEGFR3抑制剂(IC_(50)=110.4 nM)。与VEGFR1和VEGFR2相比，VEGFR3的选择性约高100倍。在此，化合物38K通过失活VEGFR3信号通路，显著抑制血管内皮生长因子-C诱导的人皮肤淋巴管内皮细胞(HDLEC)、MDA-MB-231和MDA-MB-436细胞的增殖和迁移。此外，38K还可诱导细胞凋亡，并使细胞周期中的G1/S期延长。在SD大鼠体内也表现出良好的药代动力学特征，口服生物利用度为30.9%。在体内异种移植模型中，38K通过抑制VEGFR3信号通路有效地抑制乳腺癌的生长。38K能明显抑制小鼠肺转移结节的形成。总体而言，38K可能是一种有前途的转移性乳腺癌的治疗剂。
We herein report the identification, structural optimization, and structure-activity relationship of thieno[2,3-d]pyrimidine derivatives as a novel kind of selective vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors. N-(4-Chloro-3-(trifluoromethyl)phenyl)-4-(6-(4-(4-methylpiperazin-1-yl) phenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide (38k) was the most potent VEGFR3 inhibitor (IC50 = 110.4 nM) among developed compounds. Compared with VEGFR1 and VEGFR2, VEGFR3 was approximately 100 times more selective. Here, compound 38k significantly inhibited proliferation and migration of VEGF-C-induced human dermal lymphatic endothelial cells (HDLEC), MDA-MB-231, and MDA-MB-436 cells by inactivating the VEGFR3 signaling pathway. Additionally, 38k induced cell apoptosis and a prolonged G1/S-phase in MDA-MB-231 and MDA-MB-436 cells. It also presented acceptable pharmacokinetic characteristics in Sprague-Dawley (SD) rats with an oral bioavailability of 30.9%. In the xenograft model in vivo, 38k effectively inhibited breast cancer growth by suppressing the VEGFR3 signaling pathway. 38k pronouncedly resisted the formation of pulmonary metastatic nodules in mice. Collectively, 38k may be a promising therapeutic agent of metastatic breast cancer.