Li Chuansheng, Shan Yuanyuan, Sun Ying, Si Ru, Liang Liyuan, Pan Xiaoyan, Wang Binghe, Zhang Jie
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, China.
Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Eur J Med Chem. 2017 Dec 1;141:506-518. doi: 10.1016/j.ejmech.2017.10.030. Epub 2017 Oct 12.
Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a 'triplet' inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N-(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors.
在此，我们开展了一项结构优化研究，旨在以我们之前报道的BPS-7作为先导化合物，发现第二代抗血管生成剂。基于VEGFR-2、Tie-2和EphB4高度保守的ATP结合口袋，已获得了一个包含27种化合物的文库。几种目标化合物对三种血管生成性受体酪氨酸激酶均表现出同时抑制作用。这些具有“三联体”抑制特征的化合物已被鉴定为新型抗血管生成和抗癌剂。具有代表性的VDAU11表现出显著的抗血管生成和抗癌效力，可被视为进一步优化的候选物。这些结果表明，N-(吡啶-2-基)丙烯酰胺可作为三联抑制剂的新型铰链结合基团。
