Targeting bromodomains: Epigenetic readers of lysine acetylation

Nature Reviews Drug Discovery

Volumn 13, Issue 5, 2014, Pages 337-356

  Filippakopoulos, Panagis ^a   Knapp, Stefan ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BENZODIAZEPINE DERIVATIVE; BENZOIMIDAZOLE DERIVATIVE; BET PROTEIN; BROMODOMAIN AND EXTRA TERMINAL PROTEIN; BROMODOMAIN INHIBITOR; CPI 0610; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN BINDING PROTEIN; GSK 525762; HISTONE; HISTONE DEACETYLASE INHIBITOR; ISOXAZOLE DERIVATIVE; LYSINE; OTX 015; PROTEIN INHIBITOR; PROTEIN KINASE INHIBITOR; QUINAZOLINE DERIVATIVE; QUINAZOLINONE DERIVATIVE; QUINOLINE DERIVATIVE; RVX 208; TEN 010; THIENODIAZEPINE DERIVATIVE; TRIAZOLE DERIVATIVE; TRIAZOLOBENZODIAZEPINE DERIVATIVE; TRIAZOLOPHTHALAZINE DERIVATIVE; TRIAZOLOTHIENODIAZEPINE DERIVATIVE; UNCLASSIFIED DRUG;

ACETYLATION; ATHEROSCLEROSIS; CARCINOGENESIS; CARCINOMA; DRUG EFFICACY; DRUG INDICATION; DRUG PROTEIN BINDING; DRUG SCREENING; ENZYME INHIBITION; EPIGENETICS; HEMATOLOGIC MALIGNANCY; HUMAN; INFLAMMATION; LYMPHOMA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATENT; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN PROCESSING; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; SOLID TUMOR; VIRUS INFECTION; VIRUS REPLICATION; VIRUS TRANSCRIPTION;

ACETYLATION; ANIMALS; DRUG DELIVERY SYSTEMS; EPIGENESIS, GENETIC; HUMANS; LYSINE; PROTEIN BINDING; PROTEIN STRUCTURE, TERTIARY;

EID: 84899973908     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4286     Document Type: Review

References (197)

1. Holliday, R. The inheritance of epigenetic defects. Science 238, 163-170 (1987). (Pubitemid 17139717)
2. Magnaghi-Jaulin, L. et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391, 601-605 (1998). (Pubitemid 28157604)
3. Sugita, K. et al. MLL-CBP fusion transcript in a therapy-related acute myeloid leukemia with the t(11;16)(q23;p13) which developed in an acute lymphoblastic leukemia patient with Fanconi anemia. Genes Chromosomes Cancer 27, 264-269 (2000). (Pubitemid 30067455)
4. Hennekam, R. C. Rubinstein-Taybi syndrome. Eur. J. Hum. Genet. 14, 981-985 (2006). (Pubitemid 44275830)
5. Barneda-Zahonero, B. & Parra, M. Histone deacetylases and cancer. Mol. Oncol. 6, 579-589 (2012).
6. Lee, J. H., Choy, M. L. & Marks, P. A. Mechanisms of resistance to histone deacetylase inhibitors. Adv. Cancer Res. 116, 39-86 (2012).
7. Buurman, R. et al. Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 143, 811-820.e15 (2012).
8. Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nature Rev. Drug Discov. 5, 769-784 (2006). (Pubitemid 44348499)
9. Garber, K. HDAC inhibitors overcome first hurdle. Nature Biotech. 25, 17-19 (2007). (Pubitemid 46087886)
10. McConkey, D. J., White, M. & Yan, W. HDAC inhibitor modulation of proteotoxicity as a therapeutic approach in cancer. Adv. Cancer Res. 116, 131-163 (2012).
11. Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529-533 (2011).
12. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904-917 (2011).
13. Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524-528 (2011).
14. Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119-1123 (2010).
15. Yang, Z. et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19, 535-545 (2005). (Pubitemid 41140010)
16. Bres, V., Yoh, S. M. & Jones, K. A. The multi-tasking P-TEFb complex. Curr. Opin. Cell Biol. 20, 334-340 (2008).
17. Marushige, K. Activation of chromatin by acetylation of histone side chains. Proc. Natl Acad. Sci. USA 73, 3937-3941 (1976).
18. Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844-847 (2006). (Pubitemid 43228847)
19. Celic, I. et al. The sirtuins Hst3 and Hst4p preserve genome integrity by controlling histone H3 lysine 56 deacetylation. Curr. Biol. 16, 1280-1289 (2006). (Pubitemid 43977885)
20. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693-705 (2007). (Pubitemid 46273577)
21. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074-1080 (2001). (Pubitemid 32758077)
22. Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834-840 (2009).
23. Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000-1004 (2010).
24. Kouzarides, T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 19, 1176-1179 (2000).
25. Kazantsev, A. G. & Thompson, L. M. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nature Rev. Drug Discov. 7, 854-868 (2008).
26. Thurn, K. T., Thomas, S., Moore, A. & Munster, P. N. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol. 7, 263-283 (2011).
27. Tamkun, J. W. et al. brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell 68, 561-572 (1992).
28. Yang, X. J., Ogryzko, V. V., Nishikawa, J., Howard, B. H. & Nakatani, Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382, 319-324 (1996). (Pubitemid 26260451)
29. Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491-496 (1999). (Pubitemid 29258857)
30. Gregory, G. D. et al. Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Mol. Cell. Biol. 27, 8466-8479 (2007).
31. Malik, S. & Bhaumik, S. R. Mixed lineage leukemia: histone H3 lysine 4 methyltransferases from yeast to human. FEBS J. 277, 1805-1821 (2010).
32. Trotter, K. W. & Archer, T. K. The BRG1 transcriptional coregulator. Nucl. Recept. Signal 6, e004 (2008).
33. Cavellan, E., Asp, P., Percipalle, P. & Farrants, A. K. The WSTF-SNF2h chromatin remodeling complex interacts with several nuclear proteins in transcription. J. Biol. Chem. 281, 16264-16271 (2006).
34. Venturini, L. et al. TIF1γ, a novel member of the transcriptional intermediary factor 1 family. Oncogene 18, 1209-1217 (1999). (Pubitemid 29085994)
35. Jacobson, R. H., Ladurner, A. G., King, D. S. & Tjian, R. Structure and function of a human TAFII250 double bromodomain module. Science 288, 1422-1425 (2000). (Pubitemid 30366328)
36. Xue, Y. et al. The human SWI/SNF-B chromatin-remodeling complex is related to yeast Rsc and localizes at kinetochores of mitotic chromosomes. Proc. Natl Acad. Sci. USA 97, 13015-13020 (2000).
37. Wu, S. Y. & Chiang, C. M. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J. Biol. Chem. 282, 13141-13145 (2007).
38. Muller, S., Filippakopoulos, P. & Knapp, S. Bromodomains as therapeutic targets. Expert Rev. Mol. Med. 13, e29 (2011).
39. Prinjha, R. K., Witherington, J. & Lee, K. Place your BETs: the therapeutic potential of bromodomains. Trends Pharmacol. Sci. 33, 146-153 (2012).
40. Belkina, A. C. & Denis, G. V. BET domain co-regulators in obesity, inflammation and cancer. Nature Rev. Cancer 12, 465-477 (2012).
41. Filippakopoulos, P. et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149, 214-231 (2012).
42. Owen, D. J. et al. The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase Gcn5p. EMBO J. 19, 6141-6149 (2000).
43. Moriniere, J. et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 461, 664-668 (2009).
44. Zeng, L. et al. Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. J. Am. Chem. Soc. 127, 2376-2377 (2005). (Pubitemid 40327786)
45. Sueoka, H., Kobayashi, H., Ehara, S. & Komatsu, H. Thienotriazolodiazepine compounds & medicinal uses thereof. WO 98/11111 A1 (1998).
46. Adachi, K. et al. Thienotriazolodiazepine compound and a medicinal use thereof. WO 2006/1 29623 A1 (2006).
47. Miyoshi, S., Ooike, S., Iwata, K., Hikawa, H. & Sugaraha, K. Anti tumor agent. WO 2009/084693 (2009).
48. Sachchidanand et al. Target structure-based discovery of small molecules that block human p53 and CREB binding protein association. Chem. Biol. 13, 81-90 (2006). (Pubitemid 43099926)
49. Borah, J. C. et al. A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. Chem. Biol. 18, 531-541 (2011).
50. Zhang, G. et al. Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains. J. Med. Chem. 56, 9251-9264 (2013).
51. Ito, T. et al. Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors. Chem. Biol. 18, 495-507 (2011).
52. Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067-1073 (2010).
53. Zhang, G. et al. Down-regulation of NF-KB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J. Biol. Chem. 287, 28840-28851 (2012).
54. Devaiah, B. N. et al. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc. Natl Acad. Sci. USA 109, 6927-6932 (2012).
55. Chung, C. W. et al. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J. Med. Chem. 54, 3827-3838 (2011).
56. Filippakopoulos, P. et al. Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg. Med. Chem. 20, 1878-1886 (2012).
57. Hewings, D. S. et al. 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J. Med. Chem. 54, 6761-6770 (2011).
58. Hewings, D. S. et al. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J. Med. Chem. 56, 3217-3227 (2013).
59. Bamborough, P. et al. Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides. J. Med. Chem. 55, 587-596 (2012).
60. Gehling, V. S. et al. Discovery, design, and optimization of isoxazole azepine BET inhibitors. ACS Med. Chem. Lett. 4, 835-840 (2013).
61. Hay, D. et al. The design and synthesis of 5- and 6- isoxazolylbenzimidazoles as selective inhibitors of the BET bromodomains. Medchemcomm 4, 140-144 (2013).
62. Mirguet, O. et al. Naphthyridines as novel BET family bromodomain inhibitors. ChemMedChem 9, 580-589 (2014).
63. Fish, P. V. et al. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J. Med. Chem. 55, 9831-9837 (2012).
64. Khmelnitsky, Y. L. et al. In vitro biosynthesis, isolation, and identification of predominant metabolites of 2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208). Eur. J. Med. Chem. 64, 121-128 (2013).
65. Fedorov, O. et al. [1,2,4]Triazolo[4,3-a]phthalazines: inhibitors of diverse bromodomains. J. Med. Chem. 57, 462-476 (2014).
66. Ciceri, P. et al. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nature Chem. Biol. 10, 305-312 (2014).
67. Lucas, X. et al. 4-acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew. Chem. Int. Ed Engl. 52, 14055-14059 (2013).
68. Zhao, L. et al. Fragment-based drug discovery of 2-thiazol69. Vidler, L. R. et al. Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening. J. Med. Chem. 56, 8073-8088 (2013).
69. Chung, C. W., Dean, A. W., Woolven, J. M. & Bamborough, P. Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery. J. Med. Chem. 55, 576-586 (2012).
70. Ferguson, F. M. et al. Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain. J. Med. Chem. 56, 10183-10187 (2013).
71. Vidler, L. R., Brown, N., Knapp, S. & Hoelder, S. Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites. J. Med. Chem. 55, 7346-7359 (2012).
72. Zhou, M.-M., Zeng, L. & Wang, Z. Preparation of modulators of histone acetyltransferase bromodomain binding to protein partners for use in treating viral infections by affecting transcription. WO 2006/083692 A2 (2006).
73. Sasaki, K., Ito, T., Nishino, N., Khochbin, S. & Yoshida, M. Real-time imaging of histone H4 hyperacetylation in living cells. Proc. Natl Acad. Sci. USA 106, 16257-16262 (2009).
74. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3-26 (2001). (Pubitemid 33653411)
75. Olkkola, K. T. & Ahonen, J. Midazolam and other benzodiazepines. Handb Exp. Pharmacol. 182, 335-360 (2008).
76. Verster, J. C. & Volkerts, E. R. Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature. CNS Drug Rev. 10, 45-76 (2004). (Pubitemid 38381174)
77. Sofou, K., Kristjansdottir, R., Papachatzakis, N. E., Ahmadzadeh, A. & Uvebrant, P. Management of prolonged seizures and status epilepticus in childhood: a systematic review. J. Child Neurol. 24, 918-926 (2009).
78. Quirk, K. et al. [3H]L-655,708, a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit. Neuropharmacology 35, 1331-1335 (1996). (Pubitemid 27013868)
79. Casula, M. A. et al. Identification of amino acid residues responsible for the aα5 subunit binding selectivity of L-655,708, a benzodiazepine binding site ligand at the GABAA receptor. J. Neurochem. 77, 445-451 (2001).
80. Atack, J. R. The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics. Expert Opin. Investig. Drugs 14, 601-618 (2005). (Pubitemid 40790282)
81. Korpi, E. R., Mattila, M. J., Wisden, W. & Luddens, H. GABA(A)-receptor subtypes: clinical efficacy and selectivity of benzodiazepine site ligands. Ann. Med. 29, 275-282 (1997). (Pubitemid 27399946)
82. Dubnick, B. et al. The separation of 3H-benzodiazepine binding sites in brain and of benzodiazepine pharmacological properties. Pharmacol. Biochem. Behav. 18, 311-318 (1983). (Pubitemid 13137615)
83. Richter, P. H. & Scheefeldt, U. [Synthesis and biological activity of 5-phenyl-1,3,4-benzotriazepines. 25. Synthesis of (1,2,4)triazolo(4,3-a)(1,3,4) benzotriazepines and related tricyclics]. Pharmazie 46, 701-705 (in German) (1991).
84. McDonald, I. M. et al. Novel, achiral 1,3,4-benzotriazepine analogues of 1,4-benzodiazepine-based CCK2 antagonists that display high selectivity over CCK1 receptors. J. Med. Chem. 49, 2253-2261 (2006).
85. Fernandez, P. et al. A novel indazolo-triazolo-benzotriazepine exerts anti-inflammatory effects by inhibition of cyclooxygenase-2 activity and nitric oxide synthase-2 expression. Naunyn Schmiedebergs Arch. Pharmacol. 368, 26-32 (2003). (Pubitemid 36960481)
86. Morgenstern, O. Chemistry and biological activity of 1,3,4- benzotriazepines, part 3. Pharmazie 55, 871-891 (2000).
87. Lange, B. et al. Growth factor requirements of childhood acute leukemia: establishment of GM-CSF-dependent cell lines. Blood 70, 192-199 (1987). (Pubitemid 17111261)
88. Matzuk, M. M. et al. Small-molecule inhibition of BRDT for male contraception. Cell 150, 673-684 (2012).
89. Kempen, H. Use of a thienotriazolodiazepine to increase apolipoprotein A-I levels. WO 1997/09048 A1 (1997).
90. Kempen, H. J. et al. Stimulation of hepatic apolipoprotein A-I production by novel thieno-triazolodiazepines. Lipid Insights 6, 47-54 (2013).
91. Mirguet, O. et al. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J. Med. Chem. 56, 7501-7515 (2013).
92. Mirguet, O. et al. From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151. Bioorg. Med. Chem. Lett. 22, 2963-2967 (2012).
93. Bradner, J. E. & Qi, J. Compositions and methods for treating neoplasia, inflammatory disease and other disorders. WO 2011/143669 A2 (2011).
94. Bradner, J. E. & Brown, J. Compositions and methods for modulating metabolism. WO 2011/143651 A1 (2011).
95. Bradner, J. E., Zuber, J., Shi, J. & Vakoc, C. R. Compositions and methods for treating leukemia. WO 2011/143660 A2 (2011).
96. Bradner, J. E., Matzuk, M. & Qi, J. Male contraceptive compositions and methods of use. WO 2011/143657 A1 (2011).
97. Albrecht, B. K. et al. Preparation of triazole derivatives as bromodomain inhibitors for treatment of cancers and disorders. WO 2012/075456 A1 (2012).
98. Schmees, N. et al. 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines as anticancer agents. WO 2013/030150 A1 (2013).
99. Gosmini, R. L. M. & Mirguet, O. Benzodiazepine bromodomain inhibitor. WO 2011/054553 A1 (2011).
100. Crowe, M. et al. Condensed azepine derivatives as bromodomain inhibitors. WO 2011/054844 A1 (2011).
101. Bailey, J., Gosmini, R. L. M., Mirguet, O. & Witherington, J. Benzodiazepine bromodomain inhibitor. WO 2011/054845 A1 (2011).
102. Bailey, J. M. Benzotriazolodiazepine compounds inhibitors of bromodomains. WO 2011/161031 A1 (2011).
103. Albrecht, B. K. et al. Bromodomain inhibitors and uses thereof. WO 2012/151512 A2 (2012).
104. Albrecht, B. K. et al. Bromodomain inhibitors and uses thereof. WO 2012/075383 A2 (2012).
105. Chung, C.-W. & Nicodeme, E. Bromodomain inhibitors for treating autoimmune and inflammatory diseases. WO 2011/054843 A1 (2011).
106. Seal, J. et al. Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). Bioorg. Med. Chem. Lett. 22, 2968-2972 (2012).
107. Demont, E. H., Jones, K. L. & Watson, R. J. 4-(8-methoxy-1-((1- methoxypropan-2-Yl)-2-(tetrahydro-2h-pyran-4-Yl)-1H-imidazo[4,5-C]quinolin-7-Yl) -3,5-dimethylisoxazole and its use as bromodomain inhibitor. WO 2013/024104 A1 (2013).
108. Bouillot, A. M. J. et al. Imidazo [4, 5-c] quinoline derivates as bromodomain inhibitors. WO 2011/054846 A1 (2011).
109. Demont, E. H. & Gosmini, R. L. M. Thetrahydroquinolines derivatives as bromodomain inhibitors. WO 2011/054848 A1 (2011).
110. Bamborough, P. & Chung, C. W. Novel process. WO 2011/054851 A1 (2011).
111. Picaud, S. et al. PFI-1, a highly selective protein interaction inhibitor, targeting BET bromodomains. Cancer Res. 73, 3336-3346 (2013).
112. Fish, P. V. et al. Novel heterocyclic compounds as bromodomain inhibitors. WO 2013/027168 A1 (2013).
113. Hansen, H. Compounds for the prevention and treatment of cardiovascular diseases. WO 2008/092231 A1 (2008).
114. Hansen, H. C. et al. Methods of preparing quinazolinone derivatives. WO 2009/158404 A1 (2009).
115. Hansen, H. C. et al. Novel anti-inflammatory agents. WO 2010/123975 A1 (2010).
116. Bailey, D. et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J. Am. Coll. Cardiol. 55, 2580-2589 (2010).
117. Nicholls, S. J. et al. ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies. Cardiovasc. Drugs Ther. 26, 181-187 (2012).
118. Joy, T. R. Novel HDL-based therapeutic agents. Pharmacol. Ther. 135, 18-30 (2012).
119. McLure, K. G. & Young, P. R. Preparation of substituted 2-phenyl-3H-quinazolin-4-ones and analogs as inhibitors of BET for treating cancer. WO 2013/156869 A1 (2013).
120. Picaud, S. et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl Acad. Sci. USA 110, 19754-19759 (2013).
121. McLure, K. G. et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS ONE 8, e83190 (2013).
122. Martin, M. P., Olesen, S. H., Georg, G. I. & Schonbrunn, E. Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. ACS Chem. Biol. 8, 2360-2365 (2013).
123. Dittmann, A. et al. The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains. ACS Chem. Biol. 9, 495-502 (2014).
124. Ember, S. W. et al. The acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors. ACS Chem. Biol. http://dx.doi.org/10.1021/cb500072z (2014).
125. Gaulton, A. et al. ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res. 40, D1100-D1107 (2012).
126. Albrecht, B. K., Harmange, J. C., Cote, A. & Taylor, A. M. Bromodomain inhibitors for cancer therapy. WO 2012/174487 A2 (2012).
127. Wang, L. et al. Bromodomain inhibitors. WO 2013/097601 A1 (2013).
128. Arnold, L. D., Foreman, K. W. & Werner, D. S. Bivalent bromodomain ligands and methods of using same. WO 2013/033268 A2 (2013).
129. French, C. A. et al. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 63, 304-307 (2003). (Pubitemid 36152484)
130. French, C. A. Demystified molecular pathology of NUT midline carcinomas. J. Clin. Pathol. 63, 492-496 (2010).
131. French, C. A. Pathogenesis of NUT midline carcinoma. Annu. Rev. Pathol. 7, 247-265 (2012).
132. Reynoird, N. et al. Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains. EMBO J. 29, 2943-2952 (2010).
133. Schwartz, B. E. et al. Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res. 71, 2686-2696 (2011).
134. Katsumoto, T., Yoshida, N. & Kitabayashi, I. Roles of the histone acetyltransferase monocytic leukemia zinc finger protein in normal and malignant hematopoiesis. Cancer Sci. 99, 1523-1527 (2008).
135. Ohnishi, H. et al. A complex t(1;22;11)(q44;q13;q23) translocation causing MLL-p300 fusion gene in therapy-related acute myeloid leukemia. Eur. J. Haematol. 81, 475-480 (2008).
136. Camos, M. et al. Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression. Cancer Res. 66, 6947-6954 (2006). (Pubitemid 44197669)
137. Zhang, Y. et al. Characterization of genomic breakpoints in MLL and CBP in leukemia patients with t(11;16). Genes Chromosomes Cancer 41, 257-265 (2004). (Pubitemid 39299296)
138. Iyer, N. G., Ozdag, H. & Caldas, C. p300/CBP and cancer. Oncogene 23, 4225-4231 (2004). (Pubitemid 38758588)
139. Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189-195 (2011).
140. Nebral, K. et al. Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia 23, 134-143 (2009).
141. Jang, M. K. et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 19, 523-534 (2005).
142. Gaucher, J. et al. Bromodomain-dependent stage-specific male genome programming by Brdt. EMBO J. 31, 3809-3820 (2012).
143. + T cells. J. Biol. Chem. 287, 43137-43155 (2012).
144. Chaidos, A. et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 123, 697-705 (2014).
145. Henssen, A. et al. BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget 4, 2080-2095 (2013).
146. Mertz, J. A. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108, 16669-16674 (2011).
147. Herrmann, H. et al. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem-and progenitor cells in acute myeloid leukemia AML. Oncotarget 3, 1588-1599 (2012).
148. idinones as inhibitors of the histone reader BRD4 bromodomain. J. Med. Chem. 56, 3833-3851 (2013).
149. Fiskus, W. et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myeloid leukemia (AML) cells. Mol. Cancer Ther. http://dx.doi.org/10.1158/1535-7163.MCT-13-0770 (2014).
150. Ott, C. J. et al. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood 120, 2843-2852 (2012).
151. Da Costa, D. et al. BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia. Blood Cancer J. 3, e126 (2013).
152. Roderick, J. E. et al. c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood 123, 1040-1050 (2014).
153. Cheng, Z. et al. Inhibition of BET bromodomain targets genetically diverse glioblastoma. Clin. Cancer Res. 19, 1748-1759 (2013).
154. Segura, M. F. et al. BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy. Cancer Res. 73, 6264-6276 (2013).
155. Wyce, A. et al. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 4, 2419-2429 (2013).
156. Puissant, A. et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 3, 308-323 (2013).
157. Wyce, A. et al. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLoS ONE 8, e72967 (2013).
158. Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320-334 (2013).
159. Kim, T. K. & Maniatis, T. The mechanism of transcriptional synergy of an in vitro assembled interferon-β enhanceosome. Mol. Cell 1, 119-129 (1997). (Pubitemid 127376399)
160. Spilianakis, C. G., Lalioti, M. D., Town, T., Lee, G. R. & Flavell, R. A. Interchromosomal associations between alternatively expressed loci. Nature 435, 637-645 (2005). (Pubitemid 40825504)
161. Emadali, A. et al. Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls rituximab response and tumour growth in aggressive lymphoid cancers. EMBO Mol. Med. 5, 1180-1195 (2013).
162. Pastori, C. et al. BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics 9, 611-620 (2014).
163. Stewart, H. J., Horne, G. A., Bastow, S. & Chevassut, T. J. BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1. Cancer Med. 2, 826-835 (2013).
164. Liu, S. et al. Targeting STAT5 in hematological malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2. Mol. Cancer Ther. http://dx.doi.org/10.1158/1535-7163.MCT-13-0341 (2014).
165. Wyspianska, B. S. et al. BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms. Leukemia 28, 88-97 (2014).
166. Khochbin, S. When are the BET factors the most sensitive to bromodomain inhibitors? Transcription 4, 54-57 (2013).
167. Chapuy, B. et al. Discovery and characterization of super-enhancer- associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24, 777-790 (2013).
168. Tolani, B., Gopalakrishnan, R., Punj, V., Matta, H. & Chaudhary, P. M. Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene http://dx.doi.org/10.1038/onc.2013.242 (2013).
169. Pasparakis, M. Regulation of tissue homeostasis by NF-KB signalling: implications for inflammatory diseases. Nature Rev. Immunol. 9, 778-788 (2009).
170. Huang, B., Yang, X. D., Zhou, M. M., Ozato, K. & Chen, L. F. Brd4 coactivates transcriptional activation of NF-KB via specific binding to acetylated RelA. Mol. Cell. Biol. 29, 1375-1387 (2009).
171. Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129-145 (2009).
172. Zou, Z. et al. Brd4 maintains constitutively active NF-KB in cancer cells by binding to acetylated RelA. Oncogene http://dx.doi.org/10.1038/onc.2013.179 (2013).
173. Mele, D. A. et al. BET bromodomain inhibition suppresses TH17-mediated pathology. J. Exp. Med. 210, 2181-2190 (2013).
174. + T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc. Natl Acad. Sci. USA 109, 14532-14537 (2012).
175. Mahdi, H. et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated aα-enolase in the etiology of rheumatoid arthritis. Nature Genet. 41, 1319-1324 (2009).
176. Wang, F. et al. Brd2 disruption in mice causes severe obesity without type 2 diabetes. Biochem. J. 425, 71-83 (2010).
177. Belkina, A. C., Nikolajczyk, B. S. & Denis, G. V. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J. Immunol. 190, 3670-3678 (2013).
178. Wienerroither, S. et al. Regulation of NO synthesis, local inflammation, and innate immunity to pathogens by BET family Proteins. Mol. Cell. Biol. 34, 415-427 (2014).
179. Anand, P. et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell 154, 569-582 (2013).
180. Cullen, S. J., Ponnappan, S. & Ponnappan, U. Catalytic activity of the proteasome fine-tunes Brg1-mediated chromatin remodeling to regulate the expression of inflammatory genes. Mol. Immunol. 47, 600-605 (2009).
181. Roscioli, T. et al. Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease. Nature Genet. 38, 620-622 (2006). (Pubitemid 43927301)
182. Li, Z., Guo, J., Wu, Y. & Zhou, Q. The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation. Nucleic Acids Res. 41, 277-287 (2013).
183. Bisgrove, D. A., Mahmoudi, T., Henklein, P. & Verdin, E. Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription. Proc. Natl Acad. Sci. USA 104, 13690-13695 (2007). (Pubitemid 350003382)
184. Boehm, D. et al. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle 12, 452-462 (2013).
185. Kundu, M., Guermah, M., Roeder, R. G., Amini, S. & Khalili, K. Interaction between cell cycle regulator, E2F-1, and NF-KB mediates repression of HIV-1 gene transcription. J. Biol. Chem. 272, 29468-29474 (1997). (Pubitemid 27508031)
186. Richman, D. D. et al. The challenge of finding a cure for HIV infection. Science 323, 1304-1307 (2009).
187. Karn, J. The molecular biology of HIV latency: breaking and restoring the Tat-dependent transcriptional circuit. Curr. Opin. HIV AIDS 6, 4-11 (2011).
188. Wang, X. et al. Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication. PLoS Pathog. 8, e1003021 (2012).
189. Wang, X., Helfer, C. M., Pancholi, N., Bradner, J. E. & You, J. Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA. J. Virol. 87, 3871-3884 (2013).
190. Yan, J., Li, Q., Lievens, S., Tavernier, J. & You, J. Abrogation of the Brd4-positive transcription elongation factor B complex by papillomavirus E2 protein contributes to viral oncogene repression. J. Virol. 84, 76-87 (2010).
191. Sharma, A. et al. BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proc. Natl Acad. Sci. USA 110, 12036-12041 (2013).
192. Gupta, S. S. et al. Bromo-and extraterminal domain chromatin regulators serve as cofactors for murine leukemia virus integration. J. Virol. 87, 12721-12736 (2013).
193. Gamsjaeger, R. et al. Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3. Mol. Cell. Biol. 31, 2632-2640 (2011).
194. Lamonica, J. M. et al. Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes. Proc. Natl Acad. Sci. USA 108, E159-E168 (2011).
195. Tsume, M. et al. Brd2 is required for cell cycle exit and neuronal differentiation through the E2F1 pathway in mouse neuroepithelial cells. Biochem. Biophys. Res. Commun. 425, 762-768 (2012).
196. Berkovits, B. D. & Wolgemuth, D. J. The first bromodomain of the testis-specific double bromodomain protein Brdt is required for chromocenter organization that is modulated by genetic background. Dev. Biol. 360, 358-368 (2011).
197. Liu, L., Zhen, X. T., Denton, E., Marsden, B. D. & Schapira, M. ChromoHub: a data hub for navigators of chromatin-mediated signalling. Bioinformatics 28, 2205-2206 (2012).