bromodomain containing 4 | Bromodomain kinase (BRDK) family | IUPHAR/BPS Guide to PHARMACOLOGY

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bromodomain containing 4

Target not currently curated in GtoImmuPdb

Target id: 1945

Nomenclature: bromodomain containing 4

Abbreviated Name: BRD4

Family: Bromodomain kinase (BRDK) family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1362 19 p13.1 BRD4 bromodomain containing 4
Mouse - 1400 17 B1 Brd4 bromodomain containing 4
Rat - 1403 7 q11 Brd4 bromodomain containing 4
Previous and Unofficial Names
CAP | chromosome-associated protein | HUNK1 | MCAP | Mitotic chromosome-associated protein
Database Links
BRENDA 2.7.11.1
CATH/Gene3D 1.20.920.10
ChEMBL Target CHEMBL1163125 (Hs), CHEMBL3085619 (Mm)
Ensembl Gene ENSG00000141867 (Hs), ENSMUSG00000024002 (Mm), ENSRNOG00000006770 (Rn)
Entrez Gene 23476 (Hs), 57261 (Mm), 362844 (Rn)
Human Protein Atlas ENSG00000141867 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:23476 (Hs), mmu:57261 (Mm), rno:362844 (Rn)
OMIM 608749 (Hs)
RefSeq Nucleotide NM_058243 (Hs), NM_020508 (Mm), NM_001100903 (Rn)
RefSeq Protein NP_490597 (Hs), NP_065254 (Mm), NP_001094373 (Rn)
SynPHARM 79926 (in complex with BI-2536)
79910 (in complex with BzT-7)
79940 (in complex with compound 15 (Hay et al., 2013))
80625 (in complex with compound 1 [PMID: 25408830])
79912 (in complex with compound 4d [PMID: 21851057])
81940 (in complex with compound 7d [PMID: 25703523])
83518 (in complex with CPI-0610)
79909 (in complex with GW841819X)
79916 (in complex with I-BET151)
79904 (in complex with I-BET-762)
79939 (in complex with isoxazole azepine compound 3)
79900 (in complex with (+)-JQ1)
82041 (in complex with LY 294002)
79901 (in complex with MS417)
79898 (in complex with MS436)
79925 (in complex with PFI-1)
82686 (in complex with RVX 208)
79936 (in complex with XD1)
79935 (in complex with XD14)
UniProtKB O60885 (Hs), Q9ESU6 (Mm)
Wikipedia BRD4 (Hs)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the Bromo domain 1 in human Bromodomain Containing Protein 4 (BRD4)
PDB Id:  2OSS
Resolution:  1.35Å
Species:  Human
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the first bromodomain of human BRD4 in complex with a diacetylated histone 4 peptide (H4K5acK8ac)
PDB Id:  3UVW
Resolution:  1.37Å
Species:  Human
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the first bromodomain of human BRD4 in complex with IBET-151.
PDB Id:  3ZYU
Ligand:  I-BET151
Resolution:  1.5Å
Species:  Human
References:  4
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human BRD4-BD1 in complex with the benzotriazepine ligand BzT-7
PDB Id:  3U5L
Ligand:  BzT-7
Resolution:  1.39Å
Species:  Human
References:  8
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of the first bromodomain of human BRD4 in complex with a 2-amine-9H-purine ligand
PDB Id:  4XY9
Ligand:  compound 7d [PMID: 25703523]
Resolution:  1.83Å
Species:  Human
References:  21
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-208).
PDB Id:  4MR6
Ligand:  RVX 208
Resolution:  1.67Å
Species:  Human
References:  22
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the first bromodomain of human BRD4 bound to CPI-0610.
PDB Id:  5HLS
Ligand:  CPI-0610
Resolution:  2.18Å
Species:  Human
References:  1
Enzyme Reaction
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BI-2536 Hs Inhibition 7.4 pKd 3
⤷ pKd 7.4 (Kd 3.7x10-8 M) [3]
Description: Assayed using recombinant BRD4-BD1.
(+)-JQ1 Hs Inhibition 7.3 pKd 10
⤷ pKd 7.3 (Kd 5x10-8 M) [10]
Description: Displacement binding constant to recombinant BRD4-BD1 protein.
XD14 Hs Inhibition 6.8 pKd 18
⤷ pKd 6.8 (Kd 1.6x10-7 M) [18]
Description: Assay using recombinant BRD4-BD1.
fedratinib Hs Inhibition 6.8 pKd 3
⤷ pKd 6.8 (Kd 1.64x10-7 M) [3]
BzT-7 Hs Inhibition 6.2 pKd 8
⤷ pKd 6.2 (Kd 6.4x10-7 M) [8]
Description: Measuring the dissociation constant for the compound's interaction with BD1 of BRD4.
LY 294002 Hs Inhibition 5.7 pKd 7
⤷ pKd 5.7 (Kd 1.83x10-6 M) [7]
compound 7d [PMID: 25703523] Hs Inhibition 5.3 pKd 21
⤷ pKd 5.3 (Kd 4.651x10-6 M) [21]
colchicine Hs Inhibition 4.7 pKd 18
⤷ pKd 4.7 (Kd 2x10-5 M) [18]
XD1 Hs Inhibition 4.3 pKd 18
⤷ pKd 4.3 (Kd 4.6x10-5 M) [18]
mivebresib Hs Inhibition 8.5 – 8.9 pKi 26
⤷ pKi 8.5 – 8.9 (Ki 3.5x10-9 – 1.4x10-9 M) [26]
Description: Inhibition of binding to the BD1 (8.46) or BD2 (8.85) bromodomains of human BRD4 using a TR-FRET assay.
MS436 Hs Inhibition 7.3 – 7.5 pKi 29
⤷ pKi 7.3 – 7.5 (Ki 5x10-8 – 3x10-8 M) [29]
Description: Range of inhibition of binding across both Brd1 and Brd2 bromodomains of BRD4.
molibresib Hs Inhibition 6.2 pEC50 2
⤷ pEC50 6.2 (EC50 7x10-7 M) [2]
Description: Measured in a ApoA1 reporter gene assay.
dBET6 Hs Inhibition 7.8 pIC50 27
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [27]
Description: Inhibition of BRD4 (BD1) kinase activity.
GW841819X Hs Inhibition 7.8 pIC50 2
⤷ pIC50 7.8 (IC50 1.55x10-8 M) [2]
Description: Displacement of a tetra-acetylated histone H4 peptide from the tandem BET bromodomains of BRD4.
isoxazole azepine compound 3 Hs Inhibition 7.6 pIC50 12
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [12]
Description: Assayed using recombinant BRD4-BD1.
compound 11h [PMID: 29808961] Hs Inhibition 7.6 pIC50 16
⤷ pIC50 7.6 (IC50 2.7x10-8 M) [16]
Description: Inhibition of BRD4(1).
dual BRD4/PLK1 inhibitor 23 Hs Inhibition 7.6 pIC50 17
⤷ pIC50 7.6 (IC50 2.8x10-8 M) [17]
Description: Biochemical inhibition of BRD4-BD1.
MS417 Hs Inhibition 7.5 pIC50 28
⤷ pIC50 7.5 (IC50 3x10-8 M) [28]
Description: Inhibition of MS417 binding to recombinant BRD4-BD1 using FITC-labeled MS417 as the assay probe.
molibresib Hs Inhibition 7.4 pIC50 2
⤷ pIC50 7.4 (IC50 3.61x10-8 M) [2]
Description: Displacement of a tetra-acetylated histone H4 peptide from the tandem BET bromodomains of BRD4.
CPI-203 Hs Inhibition 7.4 pIC50 6
⤷ pIC50 7.4 (IC50 3.7x10-8 M) [6]
Description: Measured using a bead-based fluorescent proximity assay.
CPI-0610 Hs Inhibition 7.4 pIC50 1
⤷ pIC50 7.4 (IC50 3.9x10-8 M) [1]
Description: IC50 vs. BRD4-BD1
compound 3 [PMID: 25408830] Hs Inhibition 7.1 pIC50 5
⤷ pIC50 7.1 (IC50 7.94x10-8 M) [5]
compound 2 [PMID: 25408830] Hs Inhibition 6.7 pIC50 5
⤷ pIC50 6.7 (IC50 2x10-7 M) [5]
PFI-1 Hs Inhibition 6.7 pIC50 11
⤷ pIC50 6.7 (IC50 2.2x10-7 M) [11]
Description: Assayed using recombinant BRD4-BD1.
compound 38 [PMID: 24000170] Hs Inhibition 6.5 pIC50 20
⤷ pIC50 6.5 (IC50 3.16x10-7 M) [20]
compound 9 [PMID: 23517011] Hs Inhibition 6.4 pIC50 14
⤷ pIC50 6.4 (IC50 3.71x10-7 M) [14]
Description: Measured using a bead-based fluorescent proximity assay assessing BRD4-BD1 interaction with acetylated histone.
compound 36 [PMID: 24000170] Hs Inhibition 6.2 pIC50 20
⤷ pIC50 6.2 (IC50 6.31x10-7 M) [20]
I-BET151 Hs Inhibition 6.1 pIC50 4
⤷ pIC50 6.1 (IC50 7.9x10-7 M) [4]
compound 15 [Hay et al., 2013] Hs Inhibition 5.9 pIC50 13
⤷ pIC50 5.9 (IC50 1.258x10-6 M) [13]
compound 6 [PMID: 30125504] Hs Inhibition 5.6 pIC50 17
⤷ pIC50 5.6 (IC50 2.579x10-6 M) [17]
Description: Biochemical inhibition of BRD4-BD1.
compound 4d [PMID: 21851057] Hs Inhibition 5.3 pIC50 15
⤷ pIC50 5.3 (IC50 4.8x10-6 M) [15]
Description: Inhibition of binding to recombinant BRD4-BD1.
compound 1 [PMID: 25408830] Hs Inhibition 4.1 pIC50 5
⤷ pIC50 4.1 (IC50 7.943x10-5 M) [5]
N-methyl-2-pyrrolidone Hs Inhibition 2.2 pIC50 24
⤷ pIC50 2.2 (IC50 6x10-3 M) [24]
Inhibitor Comments
Zhang et al. (2012) also report an IC50 for MS417 at BRD4-BD2 of 46nM [28].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
RVX 208 Hs Antagonist 7.4 pIC50 19
⤷ pIC50 7.4 (IC50 4x10-8 M) [19]
Description: Measured using a TR-FRET assay to evaluate binding to BD2 of BRD4.
General Comments
BRD4 has been reported to act as an atypical kinase, phosphorylating Ser2 present in the C-terminal domain (CTD) of RNA polymerase II, highlighting a direct role of BRD4 in transcription [6]. In certain cancers aberrant BRD4 expression mediates carcinigogenesis by hyperacetylationg the chromatin of genes involved in promoting cell proliferation. As a result, BRD4 inhibitors (and inhibitors of other BET family proteins) are being developed and investigated for therapeutic anti-cancer potential [23,25].

References

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1. Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Côté A, Leblanc Y, Nasveschuk CG, Bellon S, Bergeron L, Campbell R et al.. (2016) Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials. J. Med. Chem., 59 (4): 1330-9. [PMID:26815195]

2. Chung CW, Coste H, White JH, Mirguet O, Wilde J, Gosmini RL, Delves C, Magny SM, Woodward R, Hughes SA et al.. (2011) Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J. Med. Chem., 54 (11): 3827-38. [PMID:21568322]

3. Ciceri P, Müller S, O'Mahony A, Fedorov O, Filippakopoulos P, Hunt JP, Lasater EA, Pallares G, Picaud S, Wells C et al.. (2014) Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat. Chem. Biol., 10 (4): 305-12. [PMID:24584101]

4. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM et al.. (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature, 478 (7370): 529-33. [PMID:21964340]

5. Demont EH, Bamborough P, Chung CW, Craggs PD, Fallon D, Gordon LJ, Grandi P, Hobbs CI, Hussain J, Jones EJ et al.. (2014) 1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain. ACS Med Chem Lett, 5 (11): 1190-1195. [PMID:25408830]

6. Devaiah BN, Lewis BA, Cherman N, Hewitt MC, Albrecht BK, Robey PG, Ozato K, Sims 3rd 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): 6927-32. [PMID:22509028]

7. Dittmann A, Werner T, Chung CW, Savitski MM, Fälth Savitski M, Grandi P, Hopf C, Lindon M, Neubauer G, Prinjha RK et al.. (2014) The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains. ACS Chem. Biol., 9 (2): 495-502. [PMID:24533473]

8. Filippakopoulos P, Picaud S, Fedorov O, Keller M, Wrobel M, Morgenstern O, Bracher F, Knapp S. (2012) Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg. Med. Chem., 20 (6): 1878-86. [PMID:22137933]

9. Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Müller S, Pawson T et al.. (2012) Histone recognition and large-scale structural analysis of the human bromodomain family. Cell, 149 (1): 214-31. [PMID:22464331]

10. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I et al.. (2010) Selective inhibition of BET bromodomains. Nature, 468 (7327): 1067-73. [PMID:20871596]

11. Fish PV, Filippakopoulos P, Bish G, Brennan PE, Bunnage ME, Cook AS, Federov O, Gerstenberger BS, Jones H, Knapp S et al.. (2012) Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J. Med. Chem., 55 (22): 9831-7. [PMID:23095041]

12. Gehling VS, Hewitt MC, Vaswani RG, Leblanc Y, Côté A, Nasveschuk CG, Taylor AM, Harmange JC, Audia JE, Pardo E et al.. (2013) Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors. ACS Med Chem Lett, 4 (9): 835-40. [PMID:24900758]

13. Hay D, Fedorov O, Filippakopoulos P, Martin S, Philpott M, Picaud S, Hewings DS, Uttakar S, Heightman TD, Conway SJ et al.. (2013) The design and synthesis of 5- and 6-isoxazolylbenzimidazoles as selective inhibitors of the BET bromodomains. MedChemCommun., 4 (1): 140-144.

14. Hewings DS, Fedorov O, Filippakopoulos P, Martin S, Picaud S, Tumber A, Wells C, Olcina MM, Freeman K, Gill A et al.. (2013) Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J. Med. Chem., 56 (8): 3217-27. [PMID:23517011]

15. Hewings DS, Wang M, Philpott M, Fedorov O, Uttarkar S, Filippakopoulos P, Picaud S, Vuppusetty C, Marsden B, Knapp S et al.. (2011) 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J. Med. Chem., 54 (19): 6761-70. [PMID:21851057]

16. Li X, Zhang J, Zhao L, Yang Y, Zhang H, Zhou J. (2018) Design, Synthesis, and in vitro Biological Evaluation of 3,5-Dimethylisoxazole Derivatives as BRD4 Inhibitors. ChemMedChem, 13 (13): 1363-1368. [PMID:29808961]

17. Liu S, Yosief HO, Dai L, Huang H, Dhawan G, Zhang X, Muthengi AM, Roberts J, Buckley DL, Perry JA et al.. (2018) Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors. J. Med. Chem., 61 (17): 7785-7795. [PMID:30125504]

18. Lucas X, Wohlwend D, Hügle M, Schmidtkunz K, Gerhardt S, Schüle R, Jung M, Einsle O, Günther S. (2013) 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew. Chem. Int. Ed. Engl., 52 (52): 14055-9. [PMID:24272870]

19. McLure KG, Gesner EM, Tsujikawa L, Kharenko OA, Attwell S, Campeau E, Wasiak S, Stein A, White A, Fontano E et al.. (2013) RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS ONE, 8 (12): e83190. [PMID:24391744]

20. Mirguet O, Lamotte Y, Chung CW, Bamborough P, Delannée D, Bouillot A, Gellibert F, Krysa G, Lewis A, Witherington J et al.. (2014) Naphthyridines as novel BET family bromodomain inhibitors. ChemMedChem, 9 (3): 580-9. [PMID:24000170]

21. Picaud S, Strocchia M, Terracciano S, Lauro G, Mendez J, Daniels DL, Riccio R, Bifulco G, Bruno I, Filippakopoulos P. (2015) 9H-Purine Scaffold Reveals Induced-Fit Pocket Plasticity of the BRD9 Bromodomain. J. Med. Chem., 58 (6): 2718-36. [PMID:25703523]

22. Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M, Bountra C, Lingard H et al.. (2013) RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl. Acad. Sci. U.S.A., 110 (49): 19754-9. [PMID:24248379]

23. Pérez-Salvia M, Esteller M. (2017) Bromodomain inhibitors and cancer therapy: From structures to applications. Epigenetics, 12 (5): 323-339. [PMID:27911230]

24. Shortt J, Hsu AK, Martin BP, Doggett K, Matthews GM, Doyle MA, Ellul J, Jockel TE, Andrews DM, Hogg SJ et al.. (2014) The drug vehicle and solvent N-methylpyrrolidone is an immunomodulator and antimyeloma compound. Cell Rep, 7 (4): 1009-19. [PMID:24813887]

25. Taniguchi Y. (2016) The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins. Int J Mol Sci, 17 (11). [PMID:27827996]

26. Wang L, Pratt JK, Mcdaniel KF, Dai Y, Fidanze SD, Hasvold L, Holms JH, Kati WM, Liu D, Mantei RA et al.. (2013) Bromodomain inhibitors. Patent number: WO2013097601. Assignee: Abbvie Inc., Abbott Laboratories Trading (Shanghai) Company, Ltd.. Priority date: 30/12/2011. Publication date: 04/07/2013.

27. Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, Reyes JM, di Iulio J, Souza A, Ott CJ et al.. (2017) BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. Mol. Cell, 67 (1): 5-18.e19. [PMID:28673542]

28. Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Nevarro G, Moshkina N, Joshua J et al.. (2012) Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J. Biol. Chem., 287 (34): 28840-51. [PMID:22645123]

29. Zhang G, 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): 9251-64. [PMID:24144283]

How to cite this page

Bromodomain kinase (BRDK) family: bromodomain containing 4. Last modified on 08/11/2019. Accessed on 21/01/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1945.