Han Li-Qiang, Yuan Xia, Wu Xing-Yu, Li Ri-Dong, Xu Bo, Cheng Qing, Liu Zhen-Ming, Zhou Tian-Yan, An Hao-Yun, Wang Xin, Cheng Tie-Ming, Ge Ze-Mei, Cui Jing-Rong, Li Run-Tao
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
Zhengzhou Granlen PharmaTech, Ltd., 1300 East Hanghai Road, Zhengzhou, Henan 450016, PR China.
Eur J Med Chem. 2017 Jan 5;125:925-939. doi: 10.1016/j.ejmech.2016.10.023. Epub 2016 Oct 14.
A novel class of urea-containing peptide boronic acids as proteasome inhibitors was designed by introducing a urea scaffold to replace an amido bond. Compounds were synthesized and their antitumor activities were evaluated. After two rounds of optimizations, the compound I-14 was found to be a potent proteasome inhibitor. Compared with Bortezomib, I-14 showed higher potency against the chymotrypsin-like activity of human 20S proteasome (IC < 1 pM), similar potency against four different cancer cell lines (IC < 10 nM), and better pharmacokinetic profile. Furthermore, I-14 significantly inhibited tumor growth in Bel7404 mouse xenograft model. The excellent proteasome inhibition by I-14 was rationalized through docking and molecular dynamics studies.
通过引入脲骨架取代酰胺键，设计了一类新型含脲肽硼酸作为蛋白酶体抑制剂。合成了化合物并评估了它们的抗肿瘤活性。经过两轮优化，发现化合物I-14是一种有效的蛋白酶体抑制剂。与硼替佐米相比，I-14对人20S蛋白酶体的胰凝乳蛋白酶样活性表现出更高的效力（IC<1 pM），对四种不同癌细胞系的效力相似（IC<10 nM），并且具有更好的药代动力学特征。此外，I-14在Bel7404小鼠异种移植模型中显著抑制肿瘤生长。通过对接和分子动力学研究阐明了I-14对蛋白酶体的优异抑制作用。
