ML, Bountra C, Brennan PE, O’Mahony A, Velichko S, Mueller S, Hay D, Daniels DL,
Urh M, La Thangue NB, Kouzarides T, Prinjha R, Schwaller J, Knapp S (2015) Generation of
a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy.
Cancer Res 75(23):5106–5119. https://doi.org/10.1158/0008-5472.Can-15-0236
56. Perez-Salvia M, Esteller M (2017) Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics 12(5):323–339. https://doi.org/10.1080/15592294.2016.
1265710
57. Ember SWJ, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E
(2014) Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts
with diverse kinase inhibitors. ACS Chem Biol 9(5):1160–1171. https://doi.org/10.1021/
cb500072z
58. Ciceri P, Muller S, O’Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA,
Pallares G, Picaud S, Wells C, Martin S, Wodicka LM, Shah NP, Treiber DK, Knapp S
(2014) Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.
Nat Chem Biol 10(4):305–312. https://doi.org/10.1038/nchembio.1471
59. Ferguson FM, Fedorov O, Chaikuad A, Philpott M, Muniz JRC, Felletar I, von Delft F,
Heightman T, Knapp S, Abell C, Ciulli A (2013) Targeting low-druggability bromodomains:
fragment based screening and inhibitor design against the BAZ2B bromodomain. J Med Chem
56(24):10183–10187. https://doi.org/10.1021/jm401582c
60. Ouyang L, Zhang L, Liu J, Fu L, Yao D, Zhao Y, Zhang S, Wang G, He G, Liu B (2017)
Discovery of a small-molecule bromodomain-containing protein 4 (BRD4) inhibitor that
induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast
cancer. J Med Chem 60(24):9990–10012. https://doi.org/10.1021/acs.jmedchem.7b00275
61. Zhang GT, Plotnikov AN, Rusinova E, Shen T, Morohashi K, Joshua J, Zeng L, Mujtaba S,
Ohlmeyer M, Zhou MM (2013) Structure-guided design of potent diazobenzene inhibitors for
the BET bromodomains. J Med Chem 56(22):9251–9264. https://doi.org/10.1021/jm401334s
62. Gacias M, Gerona-Navarro G, Plotnikov AN, Zhang G, Zeng L, Kaur J, Moy G, Rusinova E,
Rodriguez Y, Matikainen B, Vincek A, Joshua J, Casaccia P, Zhou M-M (2014) Selective
chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem
Biol 21(7):841–854. https://doi.org/10.1016/j.chembiol.2014.05.009
63. Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M,
Bountra C, Lingard H, Fedorov O, Mueller S, Brennan PE, Knapp S, Filippakopoulos P (2013)
RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second
bromodomain. Proc Natl Acad Sci U S A 110(49):19754–19759. https://doi.org/10.1073/
pnas.1310658110
64. Kharenko OA, Gesner EM, Patel RG, Norek K, White A, Fontano E, Suto RK, Young PR,
McLure KG, Hansen HC (2016) RVX-297-a novel BD2 selective inhibitor of BET
bromodomains. Biochem Biophys Res Commun 477(1):62–67. https://doi.org/10.1016/j.
bbrc.2016.06.021
65. Endo J, Hikawa H, Hamada M, Ishibuchi S, Fujie N, Sugiyama N, Tanaka M, Kobayashi H,
Sugahara K, Oshita K, Iwata K, Ooike S, Murata M, Sumichika H, Chiba K, Adachi K (2016)
A phenotypic drug discovery study on thienodiazepine derivatives as inhibitors of T cell
proliferation induced by CD28 co-stimulation leads to the discovery of a first bromodomain
inhibitor. Bioorg Med Chem Lett 26(5):1365–1370. https://doi.org/10.1016/j.bmcl.2016.
01.084
66. Zuber J, Shi JW, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K,
Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P,
Bradner JE, Lowe SW, Vakoc CR (2011) RNAi screen identifies Brd4 as a therapeutic
target in acute myeloid leukaemia. Nature 478(7370):524–U124. https://doi.org/10.1038/
nature10334
67. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi JW, Jacobs HM, Kastritis E, Gilpatrick T,
Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR,
Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung
AL, Bradner JE, Mitsiades CS (2011) BET bromodomain inhibition as a therapeutic strategy
to target c-Myc. Cell 146(6):903–916. https://doi.org/10.1016/j.cell.2011.08.017
Applied Biophysics for Bromodomain Drug Discovery
331
Urh M, La Thangue NB, Kouzarides T, Prinjha R, Schwaller J, Knapp S (2015) Generation of
a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy.
Cancer Res 75(23):5106–5119. https://doi.org/10.1158/0008-5472.Can-15-0236
56. Perez-Salvia M, Esteller M (2017) Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics 12(5):323–339. https://doi.org/10.1080/15592294.2016.
1265710
57. Ember SWJ, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E
(2014) Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts
with diverse kinase inhibitors. ACS Chem Biol 9(5):1160–1171. https://doi.org/10.1021/
cb500072z
58. Ciceri P, Muller S, O’Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA,
Pallares G, Picaud S, Wells C, Martin S, Wodicka LM, Shah NP, Treiber DK, Knapp S
(2014) Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.
Nat Chem Biol 10(4):305–312. https://doi.org/10.1038/nchembio.1471
59. Ferguson FM, Fedorov O, Chaikuad A, Philpott M, Muniz JRC, Felletar I, von Delft F,
Heightman T, Knapp S, Abell C, Ciulli A (2013) Targeting low-druggability bromodomains:
fragment based screening and inhibitor design against the BAZ2B bromodomain. J Med Chem
56(24):10183–10187. https://doi.org/10.1021/jm401582c
60. Ouyang L, Zhang L, Liu J, Fu L, Yao D, Zhao Y, Zhang S, Wang G, He G, Liu B (2017)
Discovery of a small-molecule bromodomain-containing protein 4 (BRD4) inhibitor that
induces AMP-activated protein kinase-modulated autophagy-associated cell death in breast
cancer. J Med Chem 60(24):9990–10012. https://doi.org/10.1021/acs.jmedchem.7b00275
61. Zhang GT, Plotnikov AN, Rusinova E, Shen T, Morohashi K, Joshua J, Zeng L, Mujtaba S,
Ohlmeyer M, Zhou MM (2013) Structure-guided design of potent diazobenzene inhibitors for
the BET bromodomains. J Med Chem 56(22):9251–9264. https://doi.org/10.1021/jm401334s
62. Gacias M, Gerona-Navarro G, Plotnikov AN, Zhang G, Zeng L, Kaur J, Moy G, Rusinova E,
Rodriguez Y, Matikainen B, Vincek A, Joshua J, Casaccia P, Zhou M-M (2014) Selective
chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem
Biol 21(7):841–854. https://doi.org/10.1016/j.chembiol.2014.05.009
63. Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M,
Bountra C, Lingard H, Fedorov O, Mueller S, Brennan PE, Knapp S, Filippakopoulos P (2013)
RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second
bromodomain. Proc Natl Acad Sci U S A 110(49):19754–19759. https://doi.org/10.1073/
pnas.1310658110
64. Kharenko OA, Gesner EM, Patel RG, Norek K, White A, Fontano E, Suto RK, Young PR,
McLure KG, Hansen HC (2016) RVX-297-a novel BD2 selective inhibitor of BET
bromodomains. Biochem Biophys Res Commun 477(1):62–67. https://doi.org/10.1016/j.
bbrc.2016.06.021
65. Endo J, Hikawa H, Hamada M, Ishibuchi S, Fujie N, Sugiyama N, Tanaka M, Kobayashi H,
Sugahara K, Oshita K, Iwata K, Ooike S, Murata M, Sumichika H, Chiba K, Adachi K (2016)
A phenotypic drug discovery study on thienodiazepine derivatives as inhibitors of T cell
proliferation induced by CD28 co-stimulation leads to the discovery of a first bromodomain
inhibitor. Bioorg Med Chem Lett 26(5):1365–1370. https://doi.org/10.1016/j.bmcl.2016.
01.084
66. Zuber J, Shi JW, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K,
Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P,
Bradner JE, Lowe SW, Vakoc CR (2011) RNAi screen identifies Brd4 as a therapeutic
target in acute myeloid leukaemia. Nature 478(7370):524–U124. https://doi.org/10.1038/
nature10334
67. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi JW, Jacobs HM, Kastritis E, Gilpatrick T,
Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR,
Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung
AL, Bradner JE, Mitsiades CS (2011) BET bromodomain inhibition as a therapeutic strategy
to target c-Myc. Cell 146(6):903–916. https://doi.org/10.1016/j.cell.2011.08.017
Applied Biophysics for Bromodomain Drug Discovery
331