NMR fragment screening hit induces plasticity of BRD7/9 bromodomains

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• 英文论文题名：NMR fragment screening hit induces plasticity of BRD7/9 bromodomains
• 论文作者：Na Wang ; Fudong Li ; Hongyu Bao ; Jie Li ; Jihui Wu ; Ke Ruan
• 英文论文作者：Na Wang ; Fudong Li ; Hongyu Bao ; Jie Li ; Jihui Wu ; Ke Ruan ; Hefei National Laboratory for Physical Science at the Microscale ; School of Life Sciences ; University of Science and Technology of China
• 年：2016
• 作者机构：Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences,University of Science and Technology of China;
• 会议召开时间：2016-04-27
• 会议录名称：第五届中国结构生物学学术讨论会摘要集
• 语种：英文
• 分类号：Q78
• 学会代码：ZGWI
• 会议名称：第五届中国结构生物学学术讨论会
• 会议地点：中国广东深圳
• 主办单位：中国生物物理学会分子生物物理学专业委员会
• 学会名称：中国生物物理学会
• 页数：1
• 文件大小：76k
• 原文格式：D
• 会议级别：全国

摘要

The profound biology associated with BET bromodomain inhibition using chemical probes has attracted increasing attention for identification of new non-BET bromodomain inhibitors1. Several potent inhibitors to BRD9 bromodomain have been discovered and exhibited anti-cancer and antiinflammation activities very recently2,3, however, it remains unexploited regarding its paralog BRD7 bromodomain. Here, we identify new chemotypes targeting BRD7 bromodomain using NMR fragment based screening. BRD7 and BRD9 bromodomains exhibit similar patterns of chemical shift perturbations upon the titration of hit 1. The crystal structure demonstrates that hit 1 repels Y222 group of BRD9 bromodomain in a way similar to butyryllysine(Kbu) and crotonyllysine(Kcr), but not the acetyl lysine(Kac) and known inhibitors. Rearrangement of residue F161 is observed for hit 1, KAc, Kbu and Kcr successively, which provides structural insight into the new generation of chemical probes to BRD7 bromodomain.
The profound biology associated with BET bromodomain inhibition using chemical probes has attracted increasing attention for identification of new non-BET bromodomain inhibitors1. Several potent inhibitors to BRD9 bromodomain have been discovered and exhibited anti-cancer and antiinflammation activities very recently2,3, however, it remains unexploited regarding its paralog BRD7 bromodomain. Here, we identify new chemotypes targeting BRD7 bromodomain using NMR fragment based screening. BRD7 and BRD9 bromodomains exhibit similar patterns of chemical shift perturbations upon the titration of hit 1. The crystal structure demonstrates that hit 1 repels Y222 group of BRD9 bromodomain in a way similar to butyryllysine(Kbu) and crotonyllysine(Kcr), but not the acetyl lysine(Kac) and known inhibitors. Rearrangement of residue F161 is observed for hit 1, KAc, Kbu and Kcr successively, which provides structural insight into the new generation of chemical probes to BRD7 bromodomain.

引文

1 Chen,P.et al.Discovery and Characterization of GSK2801,a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B.Journal of medicinal chemistry 59,1410-1424,doi:10.1021/acs.jmedchem.5b00209(2016).
    2 Clark,P.G.et al.LP99:Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.Angewandte Chemie 54,6217-6221,doi:10.1002/anie.201501394(2015).
    3 Theodoulou,N.H.et al.Discovery of I-BRD9,a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.Journal of medicinal chemistry 59,1425-1439,doi:10.1021/acs.jmedchem.5b00256(2016).