GSTDTAP  > 地球科学
DOI10.1038/s41586-020-1930-8
Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer
Harper, Gavin; Sommerville, Roberto; Kendrick, Emma; Driscoll, Laura; Slater, Peter; Stolkin, Rustam; Walton, Allan; Christensen, Paul; Heidrich, Oliver; Lambert, Simon; Abbott, Andrew; Ryder, Karl; Gaines, Linda; Anderson, Paul
2020-01-21
发表期刊NATURE
ISSN0028-0836
EISSN1476-4687
出版年2020
卷号578期号:7794页码:306-+
文章类型Article
语种英语
国家USA
英文关键词

ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dual-bromodomain BET inhibitor ABBV-075.


Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi(1-5). Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice(6), the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions(7-9) and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported(10,11), suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment(10-13). Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075(14). Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.


领域地球科学 ; 气候变化 ; 资源环境
收录类别SCI-E
WOS记录号WOS:000508801100013
WOS关键词P-TEFB ; BRD4 ; ELONGATION ; GATA1
WOS类目Multidisciplinary Sciences
WOS研究方向Science & Technology - Other Topics
引用统计
文献类型期刊论文
条目标识符http://119.78.100.173/C666/handle/2XK7JSWQ/281439
专题地球科学
资源环境科学
气候变化
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GB/T 7714
Harper, Gavin,Sommerville, Roberto,Kendrick, Emma,et al. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer[J]. NATURE,2020,578(7794):306-+.
APA Harper, Gavin.,Sommerville, Roberto.,Kendrick, Emma.,Driscoll, Laura.,Slater, Peter.,...&Anderson, Paul.(2020).Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.NATURE,578(7794),306-+.
MLA Harper, Gavin,et al."Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer".NATURE 578.7794(2020):306-+.
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