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VEGFR-2、TIE-2和EphB4三重抑制剂作为抗血管生成和抗癌药物的发现与评估

Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents.

作者信息

Zhang Lin, Shan Yuanyuan, Ji Xingyue, Zhu Mengyuan, Li Chuansheng, Sun Ying, Si Ru, Pan Xiaoyan, Wang Jinfeng, Ma Weina, Dai Bingling, Wang Binghe, Zhang Jie

机构信息

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.

Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

出版信息

Oncotarget. 2017 Aug 8;8(62):104745-104760. doi: 10.18632/oncotarget.20065. eCollection 2017 Dec 1.

DOI:10.18632/oncotarget.20065
PMID:29285210
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5739597/
Abstract

Receptor tyrosine kinases (RTKs), especially VEGFR-2, TIE-2, and EphB4, play a crucial role in both angiogenesis and tumorigenesis. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat such pathological traits with single-target agents. Herein, we developed two classes of multi-target RTK inhibitors (RTKIs) based on the highly conserved ATP-binding pocket of VEGFR-2/TIE-2/EphB4, using previously reported BPS-7 as a lead compound. These multi-target RTKIs exhibited considerable potential as novel anti-angiogenic and anticancer agents. Among them, QDAU5 displayed the most promising potency and selectivity. It significantly suppressed viability of EA.hy926 and proliferation of several cancer cells. Further investigations indicated that QDAU5 showed high affinity to VEGFR-2 and reduced the phosphorylation of VEGFR-2. We identified QDAU5 as a potent multiple RTKs inhibitor exhibiting prominent anti-angiogenic and anticancer potency both and . Moreover, quinazolin-4(3)-one has been identified as an excellent hinge binding moiety for multi-target inhibitors of angiogenic VEGFR-2, Tie-2, and EphB4.

摘要

受体酪氨酸激酶（RTKs），尤其是血管内皮生长因子受体2（VEGFR-2）、血管生成素受体（TIE-2）和 EphB4，在血管生成和肿瘤发生过程中都起着关键作用。此外，血管生成的复杂性和异质性使得用单靶点药物治疗这些病理特征变得困难。在此，我们以先前报道的BPS-7为先导化合物，基于VEGFR-2/TIE-2/EphB4高度保守的ATP结合口袋，开发了两类多靶点RTK抑制剂（RTKIs）。这些多靶点RTKIs作为新型抗血管生成和抗癌药物显示出巨大潜力。其中，QDAU5表现出最有前景的效力和选择性。它显著抑制EA.hy926细胞的活力以及几种癌细胞的增殖。进一步研究表明，QDAU5对VEGFR-2具有高亲和力，并降低了VEGFR-2的磷酸化水平。我们确定QDAU5是一种有效的多靶点RTK抑制剂，在体内和体外均表现出显著的抗血管生成和抗癌效力。此外，喹唑啉-4(3)-酮已被确定为血管生成相关的VEGFR-2、Tie-2和EphB4多靶点抑制剂的优良铰链结合部分。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/ef8331b7ee64/oncotarget-08-104745-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/00b2d65fb258/oncotarget-08-104745-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/6e31e1652248/oncotarget-08-104745-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/0e035f547809/oncotarget-08-104745-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/2e9b53084e4e/oncotarget-08-104745-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/967e6040698d/oncotarget-08-104745-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/c51b2da9d428/oncotarget-08-104745-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/a397047acbfb/oncotarget-08-104745-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/ef8331b7ee64/oncotarget-08-104745-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/00b2d65fb258/oncotarget-08-104745-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/6e31e1652248/oncotarget-08-104745-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/0e035f547809/oncotarget-08-104745-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/2e9b53084e4e/oncotarget-08-104745-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/967e6040698d/oncotarget-08-104745-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/c51b2da9d428/oncotarget-08-104745-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/a397047acbfb/oncotarget-08-104745-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac0a/5739597/ef8331b7ee64/oncotarget-08-104745-g008.jpg

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