气候变化领域集成服务门户(CCPortal): Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation

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DOI	10.1126/science.aaz8455
	Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation
	Gilan O.; Rioja I.; Knezevic K.; Bell M.J.; Yeung M.M.; Harker N.R.; Lam E.Y.N.; Chung C.; Bamborough P.; Petretich M.; Urh M.; Atkinson S.J.; Bassil A.K.; Roberts E.J.; Vassiliadis D.; Burr M.L.; Preston A.G.S.; Wellaway C.; Werner T.; Gray J.R.; Michon A.-M.; Gobbetti T.; Kumar V.; Soden P.E.; Haynes A.; Vappiani J.; Tough D.F.; Taylor S.; Dawson S.-J.; Bantscheff M.; Lindon M.; Drewes G.; Demont E.H.; Daniels D.L.; Grandi P.; Prinjha R.K.; Dawson M.A.
发表日期	2020
ISSN	0036-8075
起始页码	387
结束页码	394
卷号	368 期号:6489
英文摘要	The two tandem bromodomains of the BET (bromodomain and extraterminal domain) 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. Copyright © 2020 The Authors,
关键词	7 (3,5 dimethyl 4 isoxazolyl) 1,3 dihydro 8 methoxy 1 [1 (2 pyridinyl)ethyl] 2h imidazo[4,5 c]quinolin 2 one apremilast bromodomain and extraterminal domain protein 1 bromodomain and extraterminal domain protein 2 bromodomain inhibitor gsk 046 gsk 620 gsk 778 transcription factor unclassified drug cancer drug gene expression immune response inhibitor physiological response acute myeloid leukemia animal experiment animal model animal tissue antibody response antineoplastic activity antiproliferative activity apoptosis Article binding affinity controlled study crystal structure drug design drug efficacy drug protein binding drug selectivity drug specificity drug structure drug targeting gene expression high throughput screening human human cell IC50 immunomodulation in vivo study inflammation K-562 cell line malignant neoplasm MDA-MB-453 cell line MOLM-13 cell line mouse nonhuman priority journal psoriasis
语种	英语
来源机构	Science
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/133547
推荐引用方式 GB/T 7714	Gilan O.,Rioja I.,Knezevic K.,et al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation[J]. Science,2020,368(6489).
APA	Gilan O..,Rioja I..,Knezevic K..,Bell M.J..,Yeung M.M..,...&Dawson M.A..(2020).Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.,368(6489).
MLA	Gilan O.,et al."Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation".368.6489(2020).