Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.
Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.
复制标题
DOI：
10.1126/science.aaz8455
复制
发表时间：
2020-04-24
期刊：
影响因子：
--
通讯作者：
Dawson MA
中科院分区：
文献类型：
--
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
BET 蛋白的两个串联溴结构域能够结合染色质以促进转录。同样抑制两种溴结构域的药物在某些恶性和炎症性疾病中显示出疗效。为了探索第一溴结构域 (BD1) 和第二溴结构域 (BD2) 在生物学和治疗中的各自功能贡献，我们开发了选择性 BD1 和 BD2 抑制剂。我们发现稳态基因表达主要需要BD1，而炎症刺激诱导的基因表达快速增加需要所有BET蛋白的BD1和BD2。 BD1 抑制剂在癌症模型中模仿了泛 BET 抑制剂的作用，而 BD2 抑制剂主要在炎症和自身免疫性疾病模型中有效。这些对 BD1 和 BD2 在维持和诱导基因表达方面的不同需求的见解可能会指导未来的 BET 靶向治疗。
The two tandem bromodomains of the BET proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1 whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET targeted therapies.
登录
查看更多内容
DOI：
10.1126/science.1249830
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baud MGJ;Lin-Shiao E;Cardote T;Tallant C;Pschibul A;Chan KH;Zengerle M;Garcia JR;Kwan TT;Ferguson FM;Ciulli A
通讯作者：
Ciulli A
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
45.3
作者：
Lewin, Jeremy;Soria, Jean-Charles;Massard, Christophe
通讯作者：
Massard, Christophe
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS
影响因子：
64.8
作者：
Faivre, Emily J.;McDaniel, Keith F.;Shen, Yu
通讯作者：
Shen, Yu