Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site.
Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site.
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DOI：
10.1021/acs.jmedchem.1c01851
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发表时间：
2022-02-10
影响因子：
7.3
通讯作者：
Zhou J
中科院分区：
文献类型：
--
作者：
Liu Z;Li Y;Chen H;Lai HT;Wang P;Wu SY;Wold EA;Leonard PG;Joseph S;Hu H;Chiang CM;Brasier AR;Tian B;Zhou J
溴域包含蛋白4(BRD4)是一种治疗顽固性炎症性疾病的新的表观遗传药物靶点。BRD4家族成员缺乏高度选择性的抑制剂，阻碍了对这一关键系统的集体理解，也阻碍了有效治疗药物的临床开发进展。在这里，我们报告了一种有效的BRD4溴域1(BD1)选择性抑制剂ZL0590(52)的发现，该抑制剂针对一个独特的、以前未报道的结合部位，同时在体外和体内显示出显著的抗炎活性。对ZL0590与人BRD4BD1形成的复合体的X射线晶体结构分析和相关的诱变研究表明，位于螺旋αB和αC界面的第一类非乙酰化赖氨酸(KAc)结合位点含有重要的BRD4残基(如Glu151)，这些残基在其他家庭成员中不常见，并且在空间上与经典的KAc识别口袋不同。这一新发现有助于进一步阐明BRD4及其蛋白质相互作用伙伴之间溴域特异性的复杂生物学基础。
Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 (52) targeting a unique, previously unreported binding site, while exhibiting significant anti-inflammatory activities in vitro and in vivo. The X-ray crystal structural analysis of ZL0590 in complex with human BRD4 BD1 and the associated mutagenesis study illustrate a first-in-class nonacetylated lysine (KAc) binding site located at the helix αB and αC interface that contains important BRD4 residues (e.g., Glu151) not commonly shared among other family members and is spatially distinct from the classic KAc recognition pocket. This new finding facilitates further elucidation of the complex biology underpinning bromodomain specificity among BRD4 and its protein–protein interaction partners.
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DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
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影响因子：
4.2
作者：
Chen, Haijun;Yang, Zhengduo;Ding, Chunyong;Chu, Lili;Zhang, Yusong;Terry, Kristin;Liu, Huiling;Shen, Qiang;Zhou, Jia
通讯作者：
Zhou, Jia
DOI：
10.1126/science.aaz8455
发表时间：
2020-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilan O;Rioja I;Knezevic K;Bell MJ;Yeung MM;Harker NR;Lam EYN;Chung CW;Bamborough P;Petretich M;Urh M;Atkinson SJ;Bassil AK;Roberts EJ;Vassiliadis D;Burr ML;Preston AGS;Wellaway C;Werner T;Gray JR;Michon AM;Gobbetti T;Kumar V;Soden PE;Haynes A;Vappiani J;Tough DF;Taylor S;Dawson SJ;Bantscheff M;Lindon M;Drewes G;Demont EH;Daniels DL;Grandi P;Prinjha RK;Dawson MA
通讯作者：
Dawson MA
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
5.4
作者：
Alamer, Edrous;Zhong, Chaojie;Hu, Haitao
通讯作者：
Hu, Haitao