68. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA
(2013) Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell
153(2):320–334. https://doi.org/10.1016/j.cell.2013.03.036
69. Berkovits BD, Wolgemuth DJ (2011) 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(2):358–368. https://doi.org/10.1016/j.ydbio.2011.10.005
70. Devaiah BN, Lewis BA, Cherman N, Hewitt MC, Albrecht BK, Robey PG, Ozato K, Sims III
RJ, Singer DS (2012) BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA
polymerase II carboxy-terminal domain. Proc Natl Acad Sci U S A 109(18):6927–6932.
https://doi.org/10.1073/pnas.1120422109
71. Urick AK, Hawk LML, Cassel MK, Mishra NK, Liu S, Adhikari N, Zhang W, Dos Santos CO,
Hall JL, Pomerantz WCK (2015) Dual screening of BPTF and Brd4 using protein-observed
fluorine NMR uncovers new bromodomain probe molecules. ACS Chem Biol 10
(10):2246–2256. https://doi.org/10.1021/acschembio.5b00483
72. Andrews FH, Singh AR, Joshi S, Smith CA, Morales GA, Garlich JR, Durden DL,
Kutateladze TG (2017) Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of
MYC to block tumor growth and metastasis. Proc Natl Acad Sci U S A 114(7):E1072–E1080.
https://doi.org/10.1073/pnas.1613091114
73. Carlino L, Rastelli G (2016) Dual kinase-bromodomain inhibitors in anticancer drug
discovery: a structural and pharmacological perspective. J Med Chem 59(20):9305–9320.
https://doi.org/10.1021/acs.jmedchem.6b00438
74. Shadrick WR, Slavish PJ, Chai SC, Connelly M, Low JA, Young BM, Bharatham N, Boyd
VA, Chen T, Lee RE, Kiplin GR, Potter PM, Waddell B, Tallant C, Knapp S, Morfouace M,
Roussel MF, Shelat AA (2018) Exploiting a water network to achieve enthalpy-driven,
bromodomain-selective BET inhibitors. Bioorg Med Chem 26:25–36
75. Vidler LR, Filippakopoulos P, Fedorov O, Picaud S, Martin S, Tomsett M, Woodward H,
Brown N, Knapp S, Hoelder S (2013) Discovery of novel small-molecule inhibitors of BRD4
using structure-based virtual screening. J Med Chem 56(20):8073–8088. https://doi.org/10.
1021/jm4011302
76. Marchand J-R, Vedove AD, Lolli G, Caflisch A (2017) Discovery of inhibitors of four
bromodomains by fragment-anchored ligand docking. J Chem Inf Model 57(10):2584–2597.
https://doi.org/10.1021/acs.jcim.7b00336
77. Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC (2017) Predictions of ligand
selectivity from absolute binding free energy calculations. J Am Chem Soc 139(2):946–957.
https://doi.org/10.1021/jacs.6b11467
78. Giblin KA, Hughes SJ, Boyd H, Hansson P, Bender A (2018) Prospectively validated
proteochemometric models for the prediction of small-molecule binding to bromodomain
proteins. J Chem Inf Model 58(9):1870–1888. https://doi.org/10.1021/acs.jcim.8b00400
79. Allen BK, Mehta S, Ember SWJ, Zhu J-Y, Schönbrunn E, Ayad NG, Schürer SC (2017)
Identification of a novel class of BRD4 inhibitors by computational screening and binding
simulations. ACS Omega 2(8):4760–4771. https://doi.org/10.1021/acsomega.7b00553
80. Ayoub AM, Hawk LML, Herzig RJ, Jiang J, Wisniewski AJ, Gee CT, Zhao P, Zhu JY,
Berndt N, Offei-Addo NK, Scott TG, Qi J, Bradner JE, Ward TR, Schonbrunn E, Georg GI,
Pomerantz WCK (2017) BET bromodomain inhibitors with one-step synthesis discovered
from virtual screen. J Med Chem 60(12):4805–4817. https://doi.org/10.1021/acs.jmedchem.
6b01336
81. Hasvold LA, Sheppard GS, Wang L, Fidanze SD, Liu D, Pratt JK, Mantei RA, Wada CK,
Hubbard R, Shen Y, Lin X, Huang X, Warder SE, Wilcox D, Li L, Buchanan FG, Smithee L,
Albert DH, Magoc TJ, Park CH, Petros AM, Panchal SC, Sun C, Kovar P, Soni NB, Elmore
SW, Kati WM, McDaniel KF (2017) Methylpyrrole inhibitors of BET bromodomains. Bioorg
Med Chem Lett 27(10):2225–2233. https://doi.org/10.1016/j.bmcl.2017.02.057
82. Harner MJ, Chauder BA, Phan J, Fesik SW (2014) Fragment-based screening of the
bromodomain of ATAD2. J Med Chem 57(22):9687–9692. https://doi.org/10.1021/
jm501035j
332
W. C. K. Pomerantz et al.
(2013) Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell
153(2):320–334. https://doi.org/10.1016/j.cell.2013.03.036
69. Berkovits BD, Wolgemuth DJ (2011) 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(2):358–368. https://doi.org/10.1016/j.ydbio.2011.10.005
70. Devaiah BN, Lewis BA, Cherman N, Hewitt MC, Albrecht BK, Robey PG, Ozato K, Sims III
RJ, Singer DS (2012) BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA
polymerase II carboxy-terminal domain. Proc Natl Acad Sci U S A 109(18):6927–6932.
https://doi.org/10.1073/pnas.1120422109
71. Urick AK, Hawk LML, Cassel MK, Mishra NK, Liu S, Adhikari N, Zhang W, Dos Santos CO,
Hall JL, Pomerantz WCK (2015) Dual screening of BPTF and Brd4 using protein-observed
fluorine NMR uncovers new bromodomain probe molecules. ACS Chem Biol 10
(10):2246–2256. https://doi.org/10.1021/acschembio.5b00483
72. Andrews FH, Singh AR, Joshi S, Smith CA, Morales GA, Garlich JR, Durden DL,
Kutateladze TG (2017) Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of
MYC to block tumor growth and metastasis. Proc Natl Acad Sci U S A 114(7):E1072–E1080.
https://doi.org/10.1073/pnas.1613091114
73. Carlino L, Rastelli G (2016) Dual kinase-bromodomain inhibitors in anticancer drug
discovery: a structural and pharmacological perspective. J Med Chem 59(20):9305–9320.
https://doi.org/10.1021/acs.jmedchem.6b00438
74. Shadrick WR, Slavish PJ, Chai SC, Connelly M, Low JA, Young BM, Bharatham N, Boyd
VA, Chen T, Lee RE, Kiplin GR, Potter PM, Waddell B, Tallant C, Knapp S, Morfouace M,
Roussel MF, Shelat AA (2018) Exploiting a water network to achieve enthalpy-driven,
bromodomain-selective BET inhibitors. Bioorg Med Chem 26:25–36
75. Vidler LR, Filippakopoulos P, Fedorov O, Picaud S, Martin S, Tomsett M, Woodward H,
Brown N, Knapp S, Hoelder S (2013) Discovery of novel small-molecule inhibitors of BRD4
using structure-based virtual screening. J Med Chem 56(20):8073–8088. https://doi.org/10.
1021/jm4011302
76. Marchand J-R, Vedove AD, Lolli G, Caflisch A (2017) Discovery of inhibitors of four
bromodomains by fragment-anchored ligand docking. J Chem Inf Model 57(10):2584–2597.
https://doi.org/10.1021/acs.jcim.7b00336
77. Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC (2017) Predictions of ligand
selectivity from absolute binding free energy calculations. J Am Chem Soc 139(2):946–957.
https://doi.org/10.1021/jacs.6b11467
78. Giblin KA, Hughes SJ, Boyd H, Hansson P, Bender A (2018) Prospectively validated
proteochemometric models for the prediction of small-molecule binding to bromodomain
proteins. J Chem Inf Model 58(9):1870–1888. https://doi.org/10.1021/acs.jcim.8b00400
79. Allen BK, Mehta S, Ember SWJ, Zhu J-Y, Schönbrunn E, Ayad NG, Schürer SC (2017)
Identification of a novel class of BRD4 inhibitors by computational screening and binding
simulations. ACS Omega 2(8):4760–4771. https://doi.org/10.1021/acsomega.7b00553
80. Ayoub AM, Hawk LML, Herzig RJ, Jiang J, Wisniewski AJ, Gee CT, Zhao P, Zhu JY,
Berndt N, Offei-Addo NK, Scott TG, Qi J, Bradner JE, Ward TR, Schonbrunn E, Georg GI,
Pomerantz WCK (2017) BET bromodomain inhibitors with one-step synthesis discovered
from virtual screen. J Med Chem 60(12):4805–4817. https://doi.org/10.1021/acs.jmedchem.
6b01336
81. Hasvold LA, Sheppard GS, Wang L, Fidanze SD, Liu D, Pratt JK, Mantei RA, Wada CK,
Hubbard R, Shen Y, Lin X, Huang X, Warder SE, Wilcox D, Li L, Buchanan FG, Smithee L,
Albert DH, Magoc TJ, Park CH, Petros AM, Panchal SC, Sun C, Kovar P, Soni NB, Elmore
SW, Kati WM, McDaniel KF (2017) Methylpyrrole inhibitors of BET bromodomains. Bioorg
Med Chem Lett 27(10):2225–2233. https://doi.org/10.1016/j.bmcl.2017.02.057
82. Harner MJ, Chauder BA, Phan J, Fesik SW (2014) Fragment-based screening of the
bromodomain of ATAD2. J Med Chem 57(22):9687–9692. https://doi.org/10.1021/
jm501035j
332
W. C. K. Pomerantz et al.