title: Discovery and structure-activity relationship studies of N6-benzoyladenine derivatives as novel BRD4 inhibitors.
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.
authors: Institute of Molecular and Cellular, Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: noguchi@iam.u-tokyo.ac.jp.
authors: Tomomi
authors: T
authors: Noguchi-Yachide
authors: Institute of Molecular and Cellular, Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors: Taki
authors: T
authors: Sakai
authors: Institute of Molecular and Cellular, Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors: Yuichi
authors: Y
authors: Hashimoto
authors: Institute of Molecular and Cellular, Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors: Takao
authors: T
authors: Yamaguchi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018797:Cell Cycle Proteins; D055808:Drug Discovery; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D000092468:Bromodomain Containing Proteins
chemical_list: D000225:Adenine; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000603429:N6-benzoyladenine
keywords: BRD4; Benzoyladenine; Bromodomain; Structure–activity relationship