BET bromodomain蛋白小分子抑制剂研究进展

柳克俊; 张智敏; 冉挺; 陈红丽; 陆涛; 陈亚东

doi:10.11665/j.issn.1000-5048.20150302

BET bromodomain蛋白小分子抑制剂研究进展

中国药科大学理学院

基金项目: 国家自然科学基金资助项目(No.81473077/H3001)；江苏省高校“青蓝工程”资助项目；江苏省普通高校研究生科研创新计划(No.CXZZ13_0337)

计量
- 文章访问数: 2609
- HTML全文浏览量: 2
- PDF下载量: 4686
出版历程
- 刊出日期: 2015-06-24

Advances in BET bromodomain protein inhibitors

摘要

摘要: 组蛋白赖氨酸乙酰化的识别是组蛋白乙酰化参与表观遗传调控的关键步骤，乙酰化的组蛋白赖氨酸可以被bromodomains(BRDs)结构域所特异性的识别，从而招募染色质调控因子到特定区域，协同完成基因表达调控。其中作用于bromodomain and extra-terminal(BET)蛋白家族的BRD结构域的小分子抑制剂在抗炎和抗肿瘤方面显示出巨大的潜力。本文通过对与BET bromodomain靶点相关的疾病、BET bromodomain结构、BET bromodomain小分子抑制剂的化学结构分类及其构效关系等多方面进行总结，为设计和开发高活性的BET bromodomain小分子抑制剂提供参考依据。
- BET /
- bromodomain /
- 小分子抑制剂 /
- 肿瘤 /
- 进展
Abstract: Recognizing acetyl-lysine of histone is a key process of epigenetic regulation that is mediated by a protein module called bromodomain(BRD). The bromodomain inhibitors of the bromodomains and extra-terminal(BET)family have shown great potential in anti-inflammatory and antiproliferative effects. Through a review of diseases and structures about BET bromodomain, different kinds of inhibitors were analyzed and their structure-activity relationships were summarized. Herenin, the recent advances reported are reviewed for discovering more excellent small molecule inhibitors.
- BET /
- bromodomain /
- small molecular inhibitors /
- tumor /
- advances

HTML全文

参考文献(52)

[1]	Zhao S,Xu W,Jiang W,et al.Regulation of cellular metabolism by protein lysine acetylation[J].Science,2010,327(5968):1000-1004.
[2]	Tony K, Montellier E, Flint SJ, et al. Acetylation: a regulatory modification to rival phosphorylation[J]? EMBO J,2000,19(6):1176-1179.
[3]	Filippakopoulos P,Picaud S,Mangos M,et al.Histone recognition and large-scale structural analysis of the human bromodomain family[J].Cell,2012,149(1):214-231.
[4]	Shein NA,Shohami E.Histone deacetylase inhibitors as therapeutic agents for acute central nervous system injuries[J].Mol Med,2011,13(3):29-39.
[5]	Gaucher J, Boussouar F, Montellier E, et al. Bromodomain-dependent stage-specific male genome programming by Brdt[J].EMBO J,2012,31(19):3809-3820.
[6]	LeRoy G,Rickards B,Flint SJ.The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription[J].Mol Cell,2008,30(1):51-60.
[7]	Denis GV,McComb ME,Faller DV,et al.Identification of transcription complexes that contain the double bromodomain protein Brd2 and chromatin remodeling machines[J].J Proteome Res,2006,5(10):502-511.
[8]	Devaiah BN,Lewis BA,Cherman N,et al.BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain[J].Proc Natl Acad Sci U S A,2012,109(18):6927-6932.
[9]	Denis GV,Green MR.A novel,mitogen-activated nuclear kinase is related to a Drosophila developmental regulator[J].Genes Dev,1996, 10(3):261-271.
[10]	French CA, Miyoshi I, Kubonishi I, et al. BRD4-NUT fusion oncogene:a novel mechanism in aggressive carcinoma[J].Cancer Res,2003, 63(2):304-307.
[11]	Delmore JE, Knapp S, Kouzarides T, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc[J].Cell,2011, 146(6):904-917.
[12]	Filippakopoulos P,Knapp S.The bromodomain interaction module[J].FEBS Lett,2012,586(17):2692-2704.
[13]	Haynes SR,Dollard C,Winston F,et al.The bromodomain:a conserved sequence found in human,Drosophila and yeast proteins [J].Nucleic Acids Res,1992,20(10):2603.
[14]	Rosner M,Hengstschlager M.Targeting epigenetic readers in cancer[J].N Engl J Med,2012,367(18):1764-1765.
[15]	Filippakopoulos P,Knapp S.The bromodomain interaction module[J].FEBS Lett,2012,586(17):2692-2704.
[16]	Winston F,Allis CD.The bromodomain:a chromatin-targeting module[J].Nat Struct Biol,1999,6(7):601-604.
[17]	Dawson MA,Kouzarides T,Huntly BJP.Targeting epigenetic readers in cancer[J].N Eng J Med,2012,367(7):647-657.
[18]	Mitsubishi Tanabe Pharma Corporation.Antitumor agent:WO,2009084693[P].2009-07-09[2015-01-14] .
[19]	Terri H,Finkel J,Wang GB.Compositions and methods for the treatment of HIV:US,20140199260[P].2014-07-17[2015-01-14] .
[20]	Dana-Farber Cancer Institute,Inc.Compositions and methods for treating neoplasia,inflammatory disease and other disorders:WO,2011143669[P].2011-11-17[2015-01-14] .
[21]	David S,Timothy PC,Laura E,et al.Progress in the development and application of small molecule inhibitors of bromodomain-acetyl-lysine interactions[J].J Med Chem,2011,55(19):9393-9413.
[22]	Filippakopoulos P,Picaud S,Fedorov O,et al.Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family[J].Bioorg Med Chem,2012,20(6):1878-1886.
[23]	Yoshitomi Pharmaceutical Industries. Thienotriazolodiazepine compounds and medicinal uses thereof:WO,1998011111[P].1998-02-19[2015-01-14] .
[24]	Zhao Y,Yang CY,Wang S,et al.The making of I-BET762,a BET bromodomain inhibitor now in clinical development[J].J Med Chem,2013,56(19):7498-7500.
[25]	Rguet O,Gosmini R,Toum J,et al.Discovery of epigenetic regulator I-BET762:lead optimization to afford a clinical candidate inhibitor of the BET bromodomains[J].J Med Chem, 2013,56(19):7501-7515.
[26]	Bayer GMBH.BET-protein-inhibitors-5-aryl-triazolo-azepine:WO,2014048945[P].2014-04-03[2015-01-14] .
[27]	Constellation Pharmaceuticals,Inc.Bromodomain inhibitors and uses thereof:WO,2012151512[P].2012-11-08[2015-01-14] .
[28]	Constellation Pharmaceuticals,Inc.Bromodomain inhibitors and uses thereof:WO,2012174487[P].2012-12-10[2015-01-14] .
[29]	Boehringer Ingelheim GMBH.Triazolopyridazine:US,20140135336 [P].2014-10-07[2014-05-15] .
[30]	Fedorov O,Lingard H,Wells C,et al.[1,2,4] Triazolo[4,3-a ] phthalazines:inhibitors of diverse bromodomains[J].J Med Chem,2014,57(2):462-476.
[31]	Hewings DS,Wang M,Philpott M,et al.3,5-Dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands[J].J Med Chem,2011,54(19):6761-6770.
[32]	Hewings DS,Fedorov O,Filippakopoulos P,et al.Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands[J].J Med Chem,2013,56(8):3217-3227.
[33]	Bamborough P,Diallo H,Goodacre JD,et al.Fragment-based discovery of bromodomain inhibitors part 2:optimization of phenylisoxazole sulfonamides[J].J Med Chem,2012,55(2):587-596.
[34]	Mirguet O,Lamotte Y,Donche F,et al.From ApoA1 upregulation to BET family bromodomain inhibition:discovery of I-BET151[J].Bioorg Med Chem Lett,2012,22(8):2963-2967.
[35]	Seal J,Lamotte Y,Donche F,et al.Identification of a novel series of BET family bromodomain inhibitors:binding mode and profile of I-BET151(GSK1210151A)[J].Bioorg Med Chem Lett,2012,22(8):2968-2972.
[36]	Glaxosmithkline LLC.Imidazo[4,5-C]quinoline derivates as bromodomain inhibitors:WO,2011054846[P].2011-05-12[2015-01-14] .
[37]	Duncan H,Oleg F,Panagis F,et al.The design and synthesis of 5-and 6-isoxazolyl benzimidazoles as selective inhibitors of the BET bromodomains[J].Med Chem Comm,2013,4(8):140-144.
[38]	Fedorov O,Martin S,Singleton DC,et al.Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains[J].J Am Chem Soc, 2013,10(37):1021-1034.
[39]	Constellation Pharmaceuticals,Inc.Bromodomain inhibitors and uses thereof:WO,2012075383[P].2012-06-07[2015-01-14] .
[40]	Victor SW,Michael CH,Rishi GV,et al.Discovery,design,and optimization of isoxazole azepine BET inhibitors[J].Med Chem Lett,2013,4(9):835-840.
[41]	Hewings DS,Wang M,Philpott M,et al.3,5-Dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands[J].J Med Chem,2011,54(10),6761-6770.
[42]	Paul VF,Panagis F,Gerwyn B,et al.Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit[J].J Med Chem, 2012,55(22):9831-9837.
[43]	Picaud S,Da C,Thanasopoulou A,et al.PFI-1,a highly selective protein interaction inhibitor,targeting BET bromodomains[J].Cancer Res,2013,73(11):3336-3346.
[44]	Chung CW,Anthony WD,James M,et al.Fragment-based discovery of bromodomain inhibitors part 1:inhibitor binding modes and implications for lead discovery[J].J Med Chem,2012,55(2):576-586.
[45]	Glaxosmithkline LLC.Tetrahydroquinolines derivatives as bromodomain inhibitors:WO,2011054848[P].2011-05-12[2015-01-14] .
[46]	McLure KG,Gesner EM,Tsujikawa L,et al.RVX-208,an inducer of ApoA-I in humans,is a BET bromodomain antagonist[J].PLoS One,2013,8(12):3190-3201.
[47]	Resverlogix Corp.Compounds for the prevention and treatment of cardiovascular diseases:WO,2008092231[P].2008-08-07[2015-01-14] .
[48]	Nicholls SJ,Gordon A,Johansson J,et al.Efficacy and safety of a novel oral inducer of apolipoprotein A-I synthesis in statin-treated patients with stable coronary artery disease:a randomized controlled trial[J].J Am Coll Cardiol,2011,57(23):1111-1119.
[49]	Bayer GMBH.BET-protein inhibitors dihydropyridopyrazinone:WO,2014095774[P].2014-06-26[2015-01-14] .
[50]	Zhao LL,Cao DY,Chen TT,et al.Fragment-based drug discovery of 2 thiazolidinones as inhibitors of the histone reader BRD4 bromodomain[J].J Med Chem, 2013,56(10):3833-3851
[51]	Abbvie,Inc.Bromodomain inhibitors:WO,2013097601[P].2013-07-04[2015-01-14] .
[52]	Lucas X,Wohlwend D,Hagle M,et al.4-Acyl pyrroles:mimicking acetylated lysines in histone code reading[J].Angew Chem Int Ed Engl,2013,52(52):14055-14059.