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Discovery and structure-activity relationship studies of N6-benzoyladenine derivatives as novel BRD4 inhibitors
Tomomi Noguchi-Yachide1, Taki Sakai1, Yuichi Hashimoto1
1Institute of Molecular and Cellular, Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Abstract:
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 0.427μM. N6-Benzoyladenine appears to be a new chemical scaffold for development of BRD4 inhibitors.
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