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bromodomain containing 2

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Target not currently curated in GtoImmuPdb

Target id: 1944

Nomenclature: bromodomain containing 2

Abbreviated Name: BRD2

Family: Bromodomain kinase (BRDK) family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 801 6p21.32 BRD2 bromodomain containing 2
Mouse - 798 17 17.98 cM Brd2 bromodomain containing 2
Rat - 798 20p12 Brd2 bromodomain containing 2
Previous and Unofficial Names Click here for help
Protein RING3 | FSRG1 | NAT
Database Links Click here for help
Alphafold
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  N-Terminal Bromodomain of Human BRD2 With IBET-151
PDB Id:  4ALG
Ligand:  I-BET151
Resolution:  1.6Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure showing BRD2-BD1 in assocation with the inhibitor BIC1.
PDB Id:  3AQA
Ligand:  BIC1
Resolution:  2.3Å
Species:  Human
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of BRD2(BD2) mutant with ligand ET bromodomain inhibitor.
PDB Id:  4QEW
Ligand:  ET bromodomain inhibitor
Resolution:  1.7Å
Species:  Human
References:  1
Image of receptor 3D structure from RCSB PDB
Description:  BRD2_Bromodomain2 complex with inhibitor 744
PDB Id:  6E6J
Ligand:  ABBV-744
Resolution:  2.44Å
Species:  Human
References:  5
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SIM1 Small molecule or natural product Hs Binding 10.5 pKd 8
pKd 10.5 (Kd 3.3x10-11 M) [8]
Description: Binding affinity for BRD2(1,2) by BROMOscan assay
ARV-771 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pKd 14
pKd 8.3 (Kd 4.7x10-9 M) [14]
Description: Binding affinity for bromodomain 2 of hBRD2.
GSK852 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.0 – 8.6 pKd 10
pKd 8.6 (Kd 2.5x10-9 M) [10]
Description: Binding affinity at BD2, determined by BROMOscan
pKd 5.0 (Kd 1x10-5 M) [10]
Description: Binding affinity at BD1, determined by BROMOscan
XD14 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 pKd 11
pKd 6.8 (Kd 1.7x10-7 M) [11]
Description: Assay using recombinant BRD2-BD1.
ME bromodomain inhibitor Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 5.8 – 6.5 pKd 1
pKd 5.8 – 6.5 (Kd 1.5x10-6 – 3x10-7 M) The higher affinity interaction is with the BRD2-BD2 domain, the lower affinity with the BRD2-BD1 domain [1]
LY 294002 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.8 pKd 4
pKd 5.8 (Kd 1.41x10-6 M) [4]
ET bromodomain inhibitor Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 4.8 – 5.1 pKd 1
pKd 4.8 – 5.1 (Kd 1.7x10-5 – 9x10-6 M) The higher affinity interaction is with the BRD2-BD1 domain, the lower affinity with the BRD2-BD2 domain [1]
BIC1 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 4.6 pKd 9
pKd 4.6 (Kd 2.8x10-5 M) [9]
Description: Binding to recombinant BRD2-BD1 protein.
GW841819X Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pIC50 2
pIC50 7.5 (IC50 2.99x10-8 M) [2]
Description: Displacement of a tetra-acetylated histone H4 peptide from the tandem BET bromodomains of BRD2.
molibresib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 2
pIC50 7.5 (IC50 3.25x10-8 M) [2]
Description: Displacement of a tetra-acetylated histone H4 peptide from the tandem BET bromodomains of BRD2.
I-BET151 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.3 pIC50 3
pIC50 6.3 (IC50 5x10-7 M) [3]
compound 38 [PMID: 24000170] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 pIC50 13
pIC50 6.3 (IC50 5.01x10-7 M) [13]
compound 36 [PMID: 24000170] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.0 pIC50 13
pIC50 6.0 (IC50 1x10-6 M) [13]
compound 4d [PMID: 21851057] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.8 pIC50 7
pIC50 5.8 (IC50 1.6x10-6 M) [7]
Description: Inhibition of binding to recombinant BRD2-BD1.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
apabetalone Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.1 pIC50 12
pIC50 7.1 (IC50 9x10-8 M) [12]
Description: Measured using a TR-FRET assay to evaluate binding to BD2 of BRD2.
General Comments
SARS-CoV-2/COVID-19
Experimental in vitro evidence, using affinity-purification mass spectrometry (AP-MS), indicates a protein-protein interaction between BRD2/4 and the SARS-CoV-2 envelope protein (E) [6], although whether this interaction is realistic based on spatial distribution of the host and viral proteins within cells was not addressed in this study. Speculatively, BRD inhibitors such as JQ1 and RVX 208, or BRD degraders (PROTACs; e.g. dBET6 or MZ1) could be utilised to examine the effect of inhibiting the BRD2/4-E interaction on SARS-CoV-2 pathobiology.

References

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1. Baud MGJ, Lin-Shiao E, Cardote T, Tallant C, Pschibul A, Chan KH, Zengerle M, Garcia JR, Kwan TT, Ferguson FM et al.. (2014) Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science, 346 (6209): 638-641. [PMID:25323695]

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. 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]

4. 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]

5. Faivre EJ, McDaniel KF, Albert DH, Mantena SR, Plotnik JP, Wilcox D, Zhang L, Bui MH, Sheppard GS, Wang L et al.. (2020) Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Nature, 578 (7794): 306-310. [PMID:31969702]

6. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL et al.. (2020) A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature, 583 (7816): 459-468. [PMID:32353859]

7. 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]

8. Imaide S, Riching KM, Makukhin N, Vetma V, Whitworth C, Hughes SJ, Trainor N, Mahan SD, Murphy N, Cowan AD et al.. (2021) Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity. Nat Chem Biol, 17 (11): 1157-1167. [PMID:34675414]

9. Ito T, Umehara T, Sasaki K, Nakamura Y, Nishino N, Terada T, Shirouzu M, Padmanabhan B, Yokoyama S, Ito A et al.. (2011) Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors. Chem Biol, 18 (4): 495-507. [PMID:21513886]

10. Lucas SCC, Atkinson SJ, Chung CW, Davis R, Gordon L, Grandi P, Gray JJR, Grimes T, Phillipou A, Preston AG et al.. (2021) Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors. J Med Chem, 64 (15): 10711-10741. [PMID:34260229]

11. 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]

12. 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]

13. 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]

14. Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM, Wang J, Chen X, Dong H, Siu K et al.. (2016) PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci USA, 113 (26): 7124-9. [PMID:27274052]

15. Seal J, Lamotte Y, Donche F, Bouillot A, Mirguet O, Gellibert F, Nicodeme E, Krysa G, Kirilovsky J, Beinke S et al.. (2012) Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). Bioorg Med Chem Lett, 22 (8): 2968-72. [PMID:22437115]

How to cite this page

Bromodomain kinase (BRDK) family: bromodomain containing 2. Last modified on 01/11/2021. Accessed on 24/06/2022. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1944.