文献类型：期刊文献

英文题名：Biological evaluation of quinoline derivatives as inhibitors of human dihydroorotate dehydrogenase

作者：Wang, Jiawei[1];Diao, Yanyan[1];Zhu, Junsheng[1];Li, Shiliang[1];Zhao, Zhenjiang[1];Li, Honglin[1];Zhu, Lili[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China

年份：2016

卷号：7

期号：5

起止页码：853

外文期刊名：MEDCHEMCOMM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000377139400012)】；

基金：This work was supported by the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (grants 21372078, 81302697, 81222046 and 81230076), the Shanghai Committee of Science and Technology (grant 14431902400), the National S&T Major Project of China (grant 2013ZX09507004) and the Twelfth Five-Year National Science&Technology Support Program (grant 2012BAI29B06). Lili Zhu is also sponsored by the Shanghai Natural Science Fund for Youth Scholars (grant 12ZR1442800). Honglin Li is also sponsored by the Innovation Program of Shanghai Municipal Education Commission (grant 13SG32) and the Fok Ying Tung Education Foundation (141035).

语种：英文

摘要：Human dihydroorotate dehydrogenase (hDHODH) is an enzyme that catalyzes the fourth step in de novo pyrimidine biosynthesis, and its inhibitors restrict the growth of rapidly proliferating cells. Therefore, hDHODH has been reported as an attractive target for the treatment of cancer and autoimmune diseases. In this study, several quinoline derivatives were identified as potent inhibitors against hDHODH, among which compound A9 was the most potent one with an IC50 value of 9.7 nM. We further verified by thermal shift assay (TSA), surface plasmon resonance (SPR) and X-ray crystallography that A9 could directly bind to the target hDHODH. The crystal structure of hDHODH in complex with compound A9 was refined to 1.90 angstrom and the binding mode of compound A9 was summarized. Moreover, structure-activity relationship (SAR) analysis of quinoline derivatives with hDHODH indicated that quinoline derivatives with a carboxyl group in R-1, a bromine atom in R-2 and a para-alkyl-substituted phenyl group in R-5, were beneficial for potency against hDHODH, which plays an important role in inhibitor design and optimization.