期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 11, 页码 2050-2054出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.04.056
关键词
PARP; PARP10; PARP14; ARTD-8; Mono(ADP-ribosyl) transferase
资金
- Johns Hopkins University Drug Discovery group
- McDaniel College Chemistry Department
- McDaniel College Student Faculty Research Fund
- Student Research and Creativity Grant
- Swedish Cancer Society [2014/716]
- Swedish Research Council [2015-04603]
- IngaBritt and Arne Lundbergs Research Foundation [403]
- European Community's Seventh Framework Programme under BioStruct-X [283570]
- Swedish Research Council [2015-04603] Funding Source: Swedish Research Council
A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with similar to 15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets. (C) 2018 Elsevier Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据