Bromodomains: Structure, function and pharmacology of inhibition

Biochemical Pharmacology

Volumn 106, Issue , 2016, Pages 1-18

  Ferri, Elena ^a   Petosa, Carlo ^b,c   McKenna, Charles E ^a  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^b UNIV GRENOBLE ALPES   (France)

^c INSTITUT DE BIOLOGIE STRUCTURALE   (France)

Author keywords

Acetylated histones; BET proteins; Bromodomains; Drug discovery; Epigenetic drugs

Indexed keywords

BROMODOMAIN; BROMODOMAIN INHIBITOR; PROTEIN DERIVATIVE; UNCLASSIFIED DRUG; (+)-JQ1 COMPOUND; ANTINEOPLASTIC AGENT; AZEPINE DERIVATIVE; BENZODIAZEPINE DERIVATIVE; CARDIOTONIC AGENT; CHROMATIN; GSK525762A; HISTONE; TRANSCRIPTION FACTOR; TRIAZOLE DERIVATIVE;

AUTOIMMUNE DISEASE; CARDIOVASCULAR DISEASE; CHIMERA; CHROMATIN; EPIGENETICS; HUMAN; INFLAMMATION; NEOPLASM; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN PROCESSING; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; ACETYLATION; ANTAGONISTS AND INHIBITORS; AUTOIMMUNE DISEASES; CARDIOVASCULAR DISEASES; CHEMICAL STRUCTURE; CHEMISTRY; CHROMATIN ASSEMBLY AND DISASSEMBLY; DRUG DEVELOPMENT; DRUG EFFECTS; GENETIC EPIGENESIS; GENETIC TRANSCRIPTION; GENETICS; METABOLISM; NEOPLASMS; PATHOLOGY;

ACETYLATION; ANTINEOPLASTIC AGENTS; AUTOIMMUNE DISEASES; AZEPINES; BENZODIAZEPINES; CARDIOTONIC AGENTS; CARDIOVASCULAR DISEASES; CHROMATIN; CHROMATIN ASSEMBLY AND DISASSEMBLY; DRUG DISCOVERY; EPIGENESIS, GENETIC; HISTONES; HUMANS; MODELS, MOLECULAR; NEOPLASMS; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC; TRIAZOLES;

EID: 84953279628     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2015.12.005     Document Type: Review

References (170)

1. K. Luger, A.W. Mader, R.K. Richmond, D.F. Sargent, and T.J. Richmond Crystal structure of the nucleosome core particle at 2.8 A resolution Nature 389 1997 251 260
2. M.A. Dawson, T. Kouzarides, and B.J. Huntly Targeting epigenetic readers in cancer N. Engl. J. Med. 367 2012 647 657
3. C.H. Waddington The epigenotype. 1942 Int. J. Epidemiol. 41 2012 10 13
4. G. Zhang, and S. Pradhan Mammalian epigenetic mechanisms IUBMB Life 66 2014 240 256
5. V.G. Allfrey, R. Faulkner, and A.E. Mirsky Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis Proc. Natl. Acad. Sci. U. S. A. 51 1964 786 794
6. P. Tessarz, and T. Kouzarides Histone core modifications regulating nucleosome structure and dynamics Nat. Rev. Mol. Cell Biol. 15 2014 703 708
7. G.E. Zentner, and S. Henikoff Regulation of nucleosome dynamics by histone modifications Nat. Struct. Mol. Biol. 20 2013 259 266
8. S. Henikoff Histone modifications: combinatorial complexity or cumulative simplicity?? Proc. Natl. Acad. Sci. U. S. A. 102 2005 5308 5309
9. B.M. Turner Cellular memory and the histone code Cell 111 2002 285 291
10. T. Jenuwein, and C.D. Allis Translating the histone code Science 293 2001 1074 1080
11. C.A. Musselman, M.E. Lalonde, J. Cote, and T.G. Kutateladze Perceiving the epigenetic landscape through histone readers Nat. Struct. Mol. Biol. 19 2012 1218 1227
12. B. Pachaiyappan, and P.M. Woster Design of small molecule epigenetic modulators Bioorg. Med. Chem. Lett. 24 2014 21 32
13. C.H. Arrowsmith, C. Bountra, P.V. Fish, K. Lee, and M. Schapira Epigenetic protein families: a new frontier for drug discovery Nat. Rev. Drug Discov. 11 2012 384 400
14. V.A. DeWoskin, and R.P. Million The epigenetics pipeline Nat. Rev. Drug Discov. 12 2013 661 662
15. P. Hunter The second coming of epigenetic drugs: a more strategic and broader research framework could boost the development of new drugs to modify epigenetic factors and gene expression EMBO Rep. 16 2015 276 279
16. A. Galvani, and C. Thiriet Nucleosome dancing at the tempo of histone tail acetylation Genes (Basel) 6 2015 607 621
17. R. Sanchez, J. Meslamani, and M.M. Zhou The bromodomain: from epigenome reader to druggable target Biochim. Biophys. Acta 1839 2014 676 685
18. J.W. Tamkun, R. Deuring, M.P. Scott, M. Kissinger, A.M. Pattatucci, T.C. Kaufman, and et al. brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2 Cell 68 1992 561 572
19. R. Sanchez, and M.M. Zhou The role of human bromodomains in chromatin biology and gene transcription Curr. Opin. Drug Discov. Dev. 12 2009 659 665
20. S. Zhao, W. Xu, W. Jiang, W. Yu, Y. Lin, T. Zhang, and et al. Regulation of cellular metabolism by protein lysine acetylation Science 327 2010 1000 1004
21. C. Choudhary, C. Kumar, F. Gnad, M.L. Nielsen, M. Rehman, T.C. Walther, and et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions Science 325 2009 834 840
22. P. Filippakopoulos, J. Qi, S. Picaud, Y. Shen, W.B. Smith, O. Fedorov, and et al. Selective inhibition of BET bromodomains Nature 468 2010 1067 1073
23. E. Nicodeme, K.L. Jeffrey, U. Schaefer, S. Beinke, S. Dewell, C.-W. Chung, and et al. Suppression of inflammation by a synthetic histone mimic Nature 468 2010 1119 1123
24. J. Shi, and C.R. Vakoc The mechanisms behind the therapeutic activity of BET bromodomain inhibition Mol. Cell 54 2014 728 736
25. C. Dhalluin, J.E. Carlson, L. Zeng, C. He, A.K. Aggarwal, and M.M. Zhou Structure and ligand of a histone acetyltransferase bromodomain Nature 399 1999 491 496
26. P. Filippakopoulos, S. Picaud, M. Mangos, T. Keates, J.P. Lambert, D. Barsyte-Lovejoy, and et al. Histone recognition and large-scale structural analysis of the human bromodomain family Cell 149 2012 214 231
27. E.M. Flynn, O.W. Huang, F. Poy, M. Oppikofer, S.F. Bellon, Y. Tang, and et al. A subset of human bromodomains recognizes butyryllysine and crotonyllysine histone peptide modifications Structure 23 2015 1801 1814
28. P. Filippakopoulos, and S. Knapp Targeting bromodomains: epigenetic readers of lysine acetylation Nat. Rev. Drug Discov. 13 2014 337 356
29. R.H. Jacobson, A.G. Ladurner, D.S. King, and R. Tjian Structure and function of a human TAFII250 double bromodomain module Science 288 2000 1422 1425
30. D.J. Owen, P. Ornaghi, J.C. Yang, N. Lowe, P.R. Evans, P. Ballario, and et al. The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p EMBO J. 19 2000 6141 6149
31. P. Filippakopoulos, and S. Knapp The bromodomain interaction module FEBS Lett. 586 2012 2692 2704
32. J. Moriniere, S. Rousseaux, U. Steuerwald, M. Soler-Lopez, S. Curtet, A.L. Vitte, and et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain Nature 461 2009 664 668
33. R. Gamsjaeger, S.R. Webb, J.M. Lamonica, A. Billin, G.A. Blobel, and J.P. Mackay Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3 Mol. Cell. Biol. 31 2011 2632 2640
34. L. Zeng, J. Li, M. Muller, S. Yan, S. Mujtaba, C. Pan, and et al. Selective small molecules blocking HIV-1 Tat and coactivator PCAF association J. Am. Chem. Soc. 127 2005 2376 2377
35. L. Sachchidanand Resnick-Silverman, S. Yan, S. Mutjaba, W.J. Liu, L. Zeng, and et al. Target structure-based discovery of small molecules that block human p53 and CREB binding protein association Chem. Biol. 13 2006 81 90
36. S. Miyoshi, S. Ooike, K. Iwata, H. Hikawa, and K. Sugahara Antitumor Agent 2009 Mitsubishi Tanabe Pharma Corporation Japan p. 37
37. O. Mirguet, R. Gosmini, J. Toum, C.A. Clement, M. Barnathan, J.M. Brusq, and et al. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains J. Med. Chem. 56 2013 7501 7515
38. C.W. Chung, H. Coste, J.H. White, O. Mirguet, J. Wilde, R.L. Gosmini, and et al. Discovery and characterization of small molecule inhibitors of the BET family bromodomains J. Med. Chem. 54 2011 3827 3838
39. M. Brand, A.M. Measures, B.G. Wilson, W.A. Cortopassi, R. Alexander, M. Hoss, and et al. Small molecule inhibitors of bromodomain-acetyl-lysine interactions ACS Chem. Biol. 10 2015 22 39
40. J.M. Garnier, P.P. Sharp, and C.J. Burns BET bromodomain inhibitors: a patent review Expert Opin. Ther. Pat. 24 2014 185 199
41. F.A. Romero, A.M. Taylor, T.D. Crawford, V. Tsui, A. Cote, and S. Magnuson Disrupting acetyl-lysine recognition: progress in the development of bromodomain inhibitors J. Med. Chem. 2015 [Epub ahead of print]
42. D. Gallenkamp, K.A. Gelato, B. Haendler, and H. Weinmann Bromodomains and their pharmacological inhibitors ChemMedChem 9 2014 438 464
43. M. Boi, E. Gaudio, P. Bonetti, I. Kwee, E. Bernasconi, C. Tarantelli, and et al. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs Clin. Cancer Res. 21 2015 1628 1638
44. E. Odore, F. Lokiec, E. Cvitkovic, M. Bekradda, P. Herait, F. Bourdel, and I. et al Phase I population pharmacokinetic assessment of the oral bromodomain inhibitor OTX015 in patients with haematologic malignancies Clin. Pharmacokinet. 2015 [Epub ahead of print]
45. M.M. Coude, T. Braun, J. Berrou, M. Dupont, S. Bertrand, A. Masse, and et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells Oncotarget 6 2015 17698 17712
46. A. Moros, V. Rodriguez, I. Saborit-Villarroya, A. Montraveta, P. Balsas, P. Sandy, and et al. Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma Leukemia 28 2014 2049 2059
47. B. King, T. Trimarchi, L. Reavie, L. Xu, J. Mullenders, P. Ntziachristos, and et al. The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability Cell 153 2013 1552 1566
48. B.N. Devaiah, B.A. Lewis, N. Cherman, M.C. Hewitt, B.K. Albrecht, P.G. Robey, and et al. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain Proc. Natl. Acad. Sci. U. S. A. 109 2012 6927 6932
49. G. Zhang, R. Liu, Y. Zhong, A.N. Plotnikov, W. Zhang, L. Zeng, and et al. Down-regulation of NF-kappaB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition J. Biol. Chem. 287 2012 28840 28851
50. N. Schmees, J. Kuhnke, B. Haendler, R. Neuhaus, P. Lejeune, S. Siegel, and et al. Preparation of 5-Aryl Triazole Azepines Useful as BET Protein Inhibitors 2014 Bayer Pharma Aktiengesellschaft Germany p. 179
51. D.S. Hewings, M. Wang, M. Philpott, O. Fedorov, S. Uttarkar, P. Filippakopoulos, and et al. 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands J. Med. Chem. 54 2011 6761 6770
52. M. Philpott, J. Yang, T. Tumber, O. Fedorov, S. Uttarkar, P. Filippakopoulos, and et al. Bromodomain-peptide displacement assays for interactome mapping and inhibitor discovery Mol. Biosyst. 7 2011 2899 2908
53. D.S. Hewings, O. Fedorov, P. Filippakopoulos, S. Martin, S. Picaud, A. Tumber, and et al. Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands J. Med. Chem. 56 2013 3217 3227
54. C.W. Chung, A.W. Dean, J.M. Woolven, and P. Bamborough Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery J. Med. Chem. 55 2012 576 586
55. P. Bamborough, H. Diallo, J.D. Goodacre, L. Gordon, A. Lewis, J.T. Seal, and et al. Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides J. Med. Chem. 55 2012 587 596
56. M.A. Dawson, R.K. Prinjha, A. Dittmann, G. Giotopoulos, M. Bantscheff, W.I. Chan, and et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia Nature 478 2011 529 533
57. O. Mirguet, Y. Lamotte, C.W. Chung, P. Bamborough, D. Delannee, A. Bouillot, and et al. Naphthyridines as novel BET family bromodomain inhibitors ChemMedChem 9 2014 580 589
58. X. Ran, Y. Zhao, L. Liu, L. Bai, C.Y. Yang, B. Zhou, and et al. Structure-based design of gamma-carboline analogues as potent and specific BET bromodomain inhibitors J. Med. Chem. 58 2015 4927 4939
59. V.S. Gehling, M.C. Hewitt, R.G. Vaswani, Y. Leblanc, A. Cote, C.G. Nasveschuk, and et al. Discovery, design, and optimization of isoxazole azepine BET inhibitors ACS Med. Chem. Lett. 4 2013 835 840
60. P.V. Fish, P. Filippakopoulos, G. Bish, P.E. Brennan, M.E. Bunnage, A.S. Cook, and 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 2012 9831 9837
61. S. Picaud, D. Da Costa, A. Thanasopoulou, P. Filippakopoulos, P.V. Fish, M. Philpott, and et al. PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains Cancer Res. 73 2013 3336 3346
62. D. Bailey, R. Jahagirdar, A. Gordon, A. Hafiane, S. Campbell, S. Chatur, and 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 2010 2580 2589
63. S. Picaud, C. Wells, I. Felletar, D. Brotherton, S. Martin, P. Savitsky, and et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain Proc. Natl. Acad. Sci. U. S. A. 110 2013 19754 19759
64. L. Zhao, D. Cao, T. Chen, Y. Wang, Z. Miao, Y. Xu, and et al. Fragment-based drug discovery of 2-thiazolidinones as inhibitors of the histone reader BRD4 bromodomain J. Med. Chem. 56 2013 3833 3851
65. L. Zhao, Y. Wang, D. Cao, T. Chen, Q. Wang, Y. Li, and et al. Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization J. Med. Chem. 58 2015 1281 1297
66. X. Lucas, D. Wohlwend, M. Hugle, K. Schmidtkunz, S. Gerhardt, R. Schule, and et al. 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading Angew. Chem. Int. Ed. Engl. 52 2013 14055 14059
67. B.C. Duffy, S. Liu, G.S. Martin, R. Wang, M.M. Hsia, H. Zhao, and et al. Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design Bioorg. Med. Chem. Lett. 25 2015 2818 2823
68. D.C. Bedford, L.H. Kasper, T. Fukuyama, and P.K. Brindle Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases Epigenetics 5 2010 9 15
69. S. Mujtaba, Y. He, L. Zeng, S. Yan, O. Plotnikova, Sachchidanand, and et al. Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation Mol. Cell. 13 2004 251 263
70. N.G. Iyer, H. Ozdag, and C. Caldas p300/CBP and cancer Oncogene 23 2004 4225 4231
71. B. Vogelstein, D. Lane, and A.J. Levine Surfing the p53 network Nature 408 2000 307 310
72. J. Li, C.A. Ghiani, J.Y. Kim, A. Liu, J. Sandoval, J. DeVellis, and et al. Inhibition of p53 transcriptional activity: a potential target for future development of therapeutic strategies for primary demyelination J. Neurosci. 28 2008 6118 6127
73. S.K. Nayak, P.S. Panesar, and H. Kumar p53-induced apoptosis and inhibitors of p53 Curr. Med. Chem. 16 2009 2627 2640
74. J.C. Borah, S. Mujtaba, I. Karakikes, L. Zeng, M. Muller, J. Patel, and et al. A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes Chem. Biol. 18 2011 531 541
75. G. Zhang, A.N. Plotnikov, E. Rusinova, T. Shen, K. Morohashi, J. Joshua, and et al. Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains J. Med. Chem. 56 2013 9251 9264
76. G. Gerona-Navarro, R. Yoel, S. Mujtaba, A. Frasca, J. Patel, L. Zeng, and et al. Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors J. Am. Chem. Soc. 133 2011 2040 2043
77. T.P. Rooney, P. Filippakopoulos, O. Fedorov, S. Picaud, W.A. Cortopassi, D.A. Hay, and et al. A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-pi interaction Angew. Chem. Int. Ed. Engl. 53 2014 6126 6130
78. D.A. Hay, O. Fedorov, S. Martin, D.C. Singleton, C. Tallant, C. Wells, and et al. Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains J. Am. Chem. Soc. 136 2014 9308 9319
79. M. Xu, A. Unzue, J. Dong, D. Spiliotopoulos, C. Nevado, and A. Caflisch Discovery of CREBBP bromodomain inhibitors by high-throughput docking and hit optimization guided by molecular dynamics J. Med. Chem. 2015 [Epub ahead of print]
80. A. Unzue, M. Xu, J. Dong, L. Wiedmer, D. Spiliotopoulos, A. Caflisch, and et al. Fragment-based design of selective nanomolar ligands of the CREBBP bromodomain J. Med. Chem. 2015 [Epub ahead of print]
81. S. Picaud, O. Fedorov, A. Thanasopoulou, K. Leonards, K. Jones, J. Meier, and et al. Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy Cancer Res. 75 2015 5106 5119
82. L.R. Vidler, N. Brown, S. Knapp, and S. Hoelder Druggability analysis and structural classification of bromodomain acetyl-lysine binding sites J. Med. Chem. 55 2012 7346 7359
83. L. Gu, S.C. Frommel, C.C. Oakes, R. Simon, K. Grupp, C.Y. Gerig, and et al. BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence Nat. Genet. 47 2015 22 30
84. I. Panagopoulos, B. Strombeck, M. Isaksson, J. Heldrup, T. Olofsson, and B. Johansson Fusion of ETV6 with an intronic sequence of the BAZ2A gene in a paediatric pre-B acute lymphoblastic leukaemia with a cryptic chromosome 12 rearrangement Br. J. Haematol. 133 2006 270 275
85. D.E. Arking, M.J. Junttila, P. Goyette, A. Huertas-Vazquez, M. Eijgelsheim, M.T. Blom, and et al. Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals PLoS Genet. 7 2011 e1002158
86. F.M. Ferguson, O. Fedorov, A. Chaikuad, M. Philpott, J.R. Muniz, I. Felletar, and et al. Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain J. Med. Chem. 56 2013 10183 10187
87. L. Drouin, S. McGrath, L.R. Vidler, A. Chaikuad, O. Monteiro, C. Tallant, and et al. Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B J. Med. Chem. 58 2015 2553 2559
88. P. Chen, A. Chaikuad, P. Bamborough, M. Bantscheff, C. Bountra, C.W. Chung, and et al. Discovery and characterization of GSK2801, a selective chemical probe for the bromodomains BAZ2A and BAZ2B J. Med. Chem. 2015 [Epub ahead of print]
89. E.H. Demont, P. Bamborough, C.W. Chung, P.D. Craggs, D. Fallon, L.J. Gordon, and et al. 1,3-Dimethyl benzimidazolones are potent, selective inhibitors of the BRPF1 bromodomain ACS Med. Chem. Lett. 5 2014 1190 1195
90. M. Ullah, N. Pelletier, L. Xiao, S.P. Zhao, K. Wang, C. Degerny, and et al. Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes Mol. Cell. Biol. 28 2008 6828 6843
91. J. Bennett, O. Fedorov, C. Tallant, O. Monteiro, J. Meier, V. Gamble, and et al. Discovery of a chemical tool inhibitor targeting the bromodomains of TRIM24 and BRPF J. Med. Chem. 2015 [Epub ahead of print]
92. B. Le Douarin, A.L. Nielsen, J.M. Garnier, H. Ichinose, F. Jeanmougin, R. Losson, and et al. A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors EMBO J. 15 1996 6701 6715
93. W.W. Tsai, Z. Wang, T.T. Yiu, K.C. Akdemir, W. Xia, S. Winter, and et al. TRIM24 links a non-canonical histone signature to breast cancer Nature 468 2010 927 932
94. K. Allton, A.K. Jain, H.M. Herz, W.W. Tsai, S.Y. Jung, J. Qin, and et al. Trim24 targets endogenous p53 for degradation Proc. Natl. Acad. Sci. U. S. A. 106 2009 11612 11616
95. L.H. Zhang, A.A. Yin, J.X. Cheng, H.Y. Huang, X.M. Li, Y.Q. Zhang, and et al. TRIM24 promotes glioma progression and enhances chemoresistance through activation of the PI3K/Akt signaling pathway Oncogene 34 2015 600 610
96. X. Liu, Y. Huang, D. Yang, X. Li, J. Liang, L. Lin, and et al. Overexpression of TRIM24 is associated with the onset and progress of human hepatocellular carcinoma PLoS One 9 2014 e85462
97. Z.F. Miao, Z.N. Wang, T.T. Zhao, Y.Y. Xu, J.H. Wu, X.Y. Liu, and et al. TRIM24 is upregulated in human gastric cancer and promotes gastric cancer cell growth and chemoresistance Virchows Arch. 466 2015 525 532
98. H. Li, L. Sun, Z. Tang, L. Fu, Y. Xu, Z. Li, and et al. Overexpression of TRIM24 correlates with tumor progression in non-small cell lung cancer PLoS One 7 2012 e37657
99. Z. Cui, W. Cao, J. Li, X. Song, L. Mao, and W. Chen TRIM24 overexpression is common in locally advanced head and neck squamous cell carcinoma and correlates with aggressive malignant phenotypes PLoS One 8 2013 e63887
100. W.S. Palmer, G. Poncet-Montange, G. Liu, A. Petrocchi, N. Reyna, G. Subramanian, and et al. Structure-guided design of IACS-9571, a selective high-affinity dual TRIM24-BRPF1 bromodomain inhibitor J. Med. Chem. 2015 [Epub ahead of print]
101. F. Boussouar, M. Jamshidikia, Y. Morozumi, S. Rousseaux, and S. Khochbin Malignant genome reprogramming by ATAD2 Biochim. Biophys. Acta 1829 2013 1010 1014
102. M.J. Harner, B.A. Chauder, J. Phan, and S.W. Fesik Fragment-based screening of the bromodomain of ATAD2 J. Med. Chem. 57 2014 9687 9692
103. C. Kadoch, D.C. Hargreaves, C. Hodges, L. Elias, L. Ho, J. Ranish, and et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy Nat. Genet. 45 2013 592 601
104. L. Scotto, G. Narayan, S.V. Nandula, S. Subramaniyam, A.M. Kaufmann, J.D. Wright, and et al. Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha Mol. Cancer 7 2008 58
105. J.U. Kang, S.H. Koo, K.C. Kwon, J.W. Park, and J.M. Kim Gain at chromosomal region 5p15.33, containing TERT, is the most frequent genetic event in early stages of non-small cell lung cancer Cancer Genet. Cytogenet. 182 2008 1 11
106. S.P. Cleary, W.R. Jeck, X. Zhao, K. Chen, S.R. Selitsky, G.L. Savich, and et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing Hepatology 58 2013 1693 1702
107. Cancer Genome Atlas Research N, C. Kandoth, N. Schultz, A.D. Cherniack, R. Akbani, Y. Liu, and et al. Integrated genomic characterization of endometria Nature 497 2013 67 73
108. Cancer Genome Atlas Research N Comprehensive genomic characterization of squamous cell lung cancers Nature 489 2012 519 525
109. C.E. Barbieri, S.C. Baca, M.S. Lawrence, F. Demichelis, M. Blattner, J.P. Theurillat, and et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer Nat. Genet. 44 2012 685 689
110. P.G. Clark, L.C. Vieira, C. Tallant, O. Fedorov, D.C. Singleton, C.M. Rogers, and et al. LP99: discovery and synthesis of the first selective BRD7/9 bromodomain inhibitor Angew. Chem. Int. Ed. Engl. 54 2015 6217 6221
111. S. Picaud, M. Strocchia, S. Terracciano, G. Lauro, J. Mendez, D.L. Daniels, and et al. 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain J. Med. Chem. 58 2015 2718 2736
112. N.H. Theodoulou, P. Bamborough, A.J. Bannister, I. Becher, R.A. Bit, K.H. Che, and et al. Discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition J. Med. Chem. 2015 [Epub ahead of print]
113. O. Fedorov, H. Lingard, C. Wells, O.P. Monteiro, S. Picaud, T. Keates, and et al. [1,2,4]Triazolo[4,3-a]phthalazines: inhibitors of diverse bromodomains J. Med. Chem. 57 2014 462 476
114. M.P. Martin, S.H. Olesen, G.I. Georg, and E. Schonbrunn Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains ACS Chem. Biol. 8 2013 2360 2365
115. S.W. Ember, J.Y. Zhu, S.H. Olesen, M.P. Martin, A. Becker, N. Berndt, and et al. Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors ACS Chem. Biol. 9 2014 1160 1171
116. P. Ciceri, S. Muller, A. O'Mahony, O. Fedorov, P. Filippakopoulos, J.P. Hunt, and et al. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology Nat. Chem. Biol. 10 2014 305 312
117. L. Chen, J.L. Yap, M. Yoshioka, M.E. Lanning, R.N. Fountain, M. Raje, and et al. BRD4 structure-activity relationships of dual PLK1 kinase/BRD4 bromodomain inhibitor BI-2536 ACS Med. Chem. Lett. 6 2015 764 769
118. A. Dittmann, T. Werner, C.W. Chung, M.M. Savitski, M. Falth Savitski, P. Grandi, and et al. The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains ACS Chem. Biol. 9 2014 495 502
119. T. Ito, H. Ando, T. Suzuki, T. Ogura, K. Hotta, Y. Imamura, and et al. Identification of a primary target of thalidomide teratogenicity Science 327 2010 1345 1350
120. G.E. Winter, D.L. Buckley, J. Paulk, J.M. Roberts, A. Souza, S. Dhe-Paganon, and et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation Science 348 2015 1376 1381
121. G. Lu, R.E. Middleton, H. Sun, M. Naniong, C.J. Ott, C.S. Mitsiades, and et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins Science 343 2014 305 309
122. J. Lu, Y. Qian, M. Altieri, H. Dong, J. Wang, K. Raina, and et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4 Chem. Biol. 22 2015 755 763
123. M. Zengerle, K.H. Chan, and A. Ciulli Selective small molecule induced degradation of the BET bromodomain protein BRD4 ACS Chem. Biol. 10 2015 1770 1777
124. A. Hammitzsch, C. Tallant, O. Fedorov, A. O'Mahony, P.E. Brennan, D.A. Hay, and et al. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses Proc. Natl. Acad. Sci. U. S. A. 112 2015 10768 10773
125. J. Drost, F. Mantovani, F. Tocco, R. Elkon, A. Comel, H. Holstege, and et al. BRD7 is a candidate tumour suppressor gene required for p53 function Nat. Cell Biol. 12 2010 380 389
126. M.M. Matzuk, M.R. McKeown, P. Filippakopoulos, Q. Li, L. Ma, J.E. Agno, and et al. Small-molecule inhibition of BRDT for male contraception Cell 150 2012 673 684
127. J. Zhu, G.D. Gaiha, S.P. John, T. Pertel, C.R. Chin, G. Gao, and et al. Reactivation of latent HIV-1 by inhibition of BRD4 Cell Rep. 2 2012 807 816
128. C. Banerjee, N. Archin, D. Michaels, A.C. Belkina, G.V. Denis, J. Bradner, and et al. BET bromodomain inhibition as a novel strategy for reactivation of HIV-1 J. Leukoc. Biol. 92 2012 1147 1154
129. Z. Li, J. Guo, Y. Wu, and Q. Zhou The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation Nucleic Acids Res. 41 2013 277 287
130. X. Wang, C.M. Helfer, N. Pancholi, J.E. Bradner, and J. You Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA J. Virol. 87 2013 3871 3884
131. D. Boehm, V. Calvanese, R.D. Dar, S. Xing, S. Schroeder, L. Martins, and et al. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism Cell Cycle 12 2013 452 462
132. B. Tolani, R. Gopalakrishnan, V. Punj, H. Matta, and P.M. Chaudhary Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors Oncogene 33 2014 2928 2937
133. X. Wang, J. Li, R.M. Schowalter, J. Jiao, C.B. Buck, and J. You Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication PLoS Pathog. 8 2012 e1003021
134. J. Loven, H.A. Hoke, C.Y. Lin, A. Lau, D.A. Orlando, C.R. Vakoc, and et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers Cell 153 2013 320 334
135. J.E. Delmore, G.C. Issa, M.E. Lemieux, P.B. Rahl, J. Shi, H.M. Jacobs, and et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc Cell 146 2011 904 917
136. A. Chaidos, V. Caputo, and A. Karadimitris Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence Ther. Adv. Hematol. 6 2015 128 141
137. M.C. Morris, E.A. Gilliam, and L. Li Innate immune programing by endotoxin and its pathological consequences Front. Immunol. 5 2014 680
138. Y. Xiao, L. Liang, M. Huang, Q. Qiu, S. Zeng, M. Shi, and et al. Bromodomain and extra-terminal domain bromodomain inhibition prevents synovial inflammation via blocking IkappaB kinase-dependent NF-kappaB activation in rheumatoid fibroblast-like synoviocytes Rheumatology (Oxford) 55 2016 173 184
139. A.C. Belkina, B.S. Nikolajczyk, and G.V. Denis BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses J. Immunol. 190 2013 3670 3678
140. A. Nadeem, N.O. Al-Harbi, M.M. Al-Harbi, A.M. El-Sherbeeny, S.F. Ahmad, N. Siddiqui, and et al. Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation Pharmacol. Res. 99 2015 248 257
141. Y.M. Khan, P. Kirkham, P.J. Barnes, and I.M. Adcock Brd4 is essential for IL-1beta-induced inflammation in human airway epithelial cells PLoS One 9 2014 e95051
142. P.A. Toniolo, S. Liu, J.E. Yeh, P.M. Moraes-Vieira, S.R. Walker, V. Vafaizadeh, and et al. Inhibiting STAT5 by the BET bromodomain inhibitor JQ1 disrupts human dendritic cell maturation J. Immunol. 194 2015 3180 3190
143. D.A. Mele, A. Salmeron, S. Ghosh, H.R. Huang, B.M. Bryant, and J.M. Lora BET bromodomain inhibition suppresses TH17-mediated pathology J. Exp. Med. 210 2013 2181 2190
144. T. Fujita, and Y. Ishikawa Apoptosis in heart failure. The role of the beta-adrenergic receptor-mediated signaling pathway and p53-mediated signaling pathway in the apoptosis of cardiomyocytes Circ. J. 75 2011 1811 1818
145. P. Anand, J.D. Brown, C.Y. Lin, J. Qi, R. Zhang, P.C. Artero, and et al. BET bromodomains mediate transcriptional pause release in heart failure Cell 154 2013 569 582
146. J.I. Spiltoir, M.S. Stratton, M.A. Cavasin, K. Demos-Davies, B.G. Reid, J. Qi, and et al. BET acetyl-lysine binding proteins control pathological cardiac hypertrophy J. Mol. Cell. Cardiol. 63 2013 175 179
147. R. Jahagirdar, H. Zhang, S. Azhar, J. Tobin, S. Attwell, R. Yu, and et al. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice Atherosclerosis 236 2014 91 100
148. S.J. Nicholls, R. Puri, K. Wolski, C.M. Ballantyne, P.J. Barter, H.B. Brewer, and et al. Effect of the BET protein inhibitor, RVX-208, on progression of coronary atherosclerosis: results of the phase 2b, randomized, double-blind, multicenter, ASSURE trial Am. J. Cardiovasc. Drugs 2015 [Epub ahead of print]
149. E. Korb, M. Herre, I. Zucker-Scharff, R.B. Darnell, and C.D. Allis BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice Nat. Neurosci. 18 2015 1464 1473
150. M.G. Baud, E. Lin-Shiao, T. Cardote, C. Tallant, A. Pschibul, K.H. Chan, and et al. Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes Science 346 2014 638 641
151. Y. Zhan, M. Kost-Alimova, X. Shi, E. Leo, J.P. Bardenhagen, H.E. Shepard, and et al. Development of novel cellular histone-binding and chromatin-displacement assays for bromodomain drug discovery Epigenet. Chromatin 8 2015 37
152. G.A. Josling, M. Petter, S.C. Oehring, A.P. Gupta, O. Dietz, D.W. Wilson, and et al. A Plasmodium falciparum bromodomain protein regulates invasion gene expression Cell Host Microbe 17 2015 741 751
153. W. Fiskus, S. Sharma, J. Qi, B. Shah, S.G. Devaraj, C. Leveque, and et al. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD Mol. Cancer Ther. 13 2014 2315 2327
154. S. Liu, S.R. Walker, E.A. Nelson, R. Cerulli, M. Xiang, P.A. Toniolo, and et al. Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2 Mol. Cancer Ther. 13 2014 1194 1205
155. B. Sun, B. Shah, W. Fiskus, J. Qi, K. Rajapakshe, C. Coarfa, and et al. Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib Blood 126 2015 1565 1574
156. M. Ceribelli, P.N. Kelly, A.L. Shaffer, G.W. Wright, W. Xiao, Y. Yang, and et al. Blockade of oncogenic IkappaB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors Proc. Natl. Acad. Sci. U. S. A. 111 2014 11365 11370
157. T.J. Stuhlmiller, S.M. Miller, J.S. Zawistowski, K. Nakamura, A.S. Beltran, J.S. Duncan, and et al. Inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting BET family bromodomains Cell Rep. 11 2015 390 404
158. E.E. Stratikopoulos, M. Dendy, M. Szabolcs, A.J. Khaykin, C. Lefebvre, M.M. Zhou, and et al. Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy Cancer Cell 27 2015 837 851
159. C. Wong, S.V. Laddha, L. Tang, E. Vosburgh, A.J. Levine, E. Normant, and et al. The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors Cell Death Dis. 5 2014 e1450
160. D.H. Lee, J. Qi, J.E. Bradner, J.W. Said, N.B. Doan, C. Forscher, and et al. Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma Int. J. Cancer 136 2015 2055 2064
161. W. Fiskus, S. Sharma, J. Qi, J.A. Valenta, L.J. Schaub, B. Shah, and et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells Mol. Cancer Ther. 13 2014 1142 1154
162. J. Bhadury, L.M. Nilsson, S.V. Muralidharan, L.C. Green, Z. Li, E.M. Gesner, and et al. BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma Proc. Natl. Acad. Sci. U. S. A. 111 2014 E2721 E2730
163. A. Heinemann, C. Cullinane, R. De Paoli-Iseppi, J.S. Wilmott, D. Gunatilake, J. Madore, and et al. Combining BET and HDAC inhibitors synergistically induces apoptosis of melanoma and suppresses AKT and YAP signaling Oncotarget 6 2015 21507 21521
164. P.K. Mazur, A. Herner, S.S. Mello, M. Wirth, S. Hausmann, F.J. Sanchez-Rivera, and et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma Nat. Med. 21 2015 1163 1171
165. Y.S. Lai, J.Y. Chen, H.J. Tsai, T.Y. Chen, and W.C. Hung The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells Blood Cancer J. 5 2015 e313
166. M.B. Siegel, S.Q. Liu, M.A. Davare, S.E. Spurgeon, M.M. Loriaux, B.J. Druker, and et al. Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma Oncotarget 6 2015 18921 18932
167. R. Gopalakrishnan, H. Matta, B. Tolani, T. Triche Jr., and P.M. Chaudhary Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors Oncogene 2015 [Epub ahead of print]
168. A. Emadali, S. Rousseaux, J. Bruder-Costa, C. Rome, S. Duley, S. Hamaidia, and 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 2013 1180 1195
169. P. Rathert, M. Roth, T. Neumann, F. Muerdter, J.S. Roe, M. Muhar, and et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition Nature 525 2015 543 547
170. C.Y. Fong, O. Gilan, E.Y. Lam, A.F. Rubin, S. Ftouni, D. Tyler, and et al. BET inhibitor resistance emerges from leukaemia stem cells Nature 525 2015 538 542