Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 5, Pages 953-959Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.01.022
Keywords
BRD4; Bromodomain; Benzoyladenine; Structure-activity relationship
Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [26293025, 26810091] Funding Source: KAKEN
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Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetylated lysines in histones. Among them, BRD4 is a candidate target molecule of therapeutic agents for diverse diseases, including cancer and inflammatory disease. As a part of our continuing structural development studies of thalidomide to obtain a broad spectrum of biological modifiers based on the 'multi-template' approach, in this work we focused on BRD4-inhibitory activity, and discovered that N6-benzoyladenine derivatives exhibit this activity. Structure-activity relationship studies led to N6-(2,4,5-trimethoxybenzoyl) adenine (29), which exhibits potent BRD4 bromodomain1 inhibitory activity with an IC50 value of 0.427 mu M. N6-Benzoyladenine appears to be a new chemical scaffold for development of BRD4 inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.
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