Target Information
| Target General Information | Top | |||||
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| Target ID |
T40556
(Former ID: TTDI02032)
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| Target Name |
Bromodomain-containing protein 4 (BRD4)
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| Synonyms |
Protein HUNK1; HUNK1
Click to Show/Hide
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| Gene Name |
BRD4
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Myeloproliferative neoplasm [ICD-11: 2A20] | |||||
| Function |
Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P-TEFb complex and recruiting it to promoters. Also recruits P-TEFb complex to distal enhancers, so called anti-pause enhancers in collaboration with JMJD6. BRD4 and JMJD6 are required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo. In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters.
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| BioChemical Class |
Bromodomain
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| UniProt ID | ||||||
| Sequence |
MSAESGPGTRLRNLPVMGDGLETSQMSTTQAQAQPQPANAASTNPPPPETSNPNKPKRQT
NQLQYLLRVVLKTLWKHQFAWPFQQPVDAVKLNLPDYYKIIKTPMDMGTIKKRLENNYYW NAQECIQDFNTMFTNCYIYNKPGDDIVLMAEALEKLFLQKINELPTEETEIMIVQAKGRG RGRKETGTAKPGVSTVPNTTQASTPPQTQTPQPNPPPVQATPHPFPAVTPDLIVQTPVMT VVPPQPLQTPPPVPPQPQPPPAPAPQPVQSHPPIIAATPQPVKTKKGVKRKADTTTPTTI DPIHEPPSLPPEPKTTKLGQRRESSRPVKPPKKDVPDSQQHPAPEKSSKVSEQLKCCSGI LKEMFAKKHAAYAWPFYKPVDVEALGLHDYCDIIKHPMDMSTIKSKLEAREYRDAQEFGA DVRLMFSNCYKYNPPDHEVVAMARKLQDVFEMRFAKMPDEPEEPVVAVSSPAVPPPTKVV APPSSSDSSSDSSSDSDSSTDDSEEERAQRLAELQEQLKAVHEQLAALSQPQQNKPKKKE KDKKEKKKEKHKRKEEVEENKKSKAKEPPPKKTKKNNSSNSNVSKKEPAPMKSKPPPTYE SEEEDKCKPMSYEEKRQLSLDINKLPGEKLGRVVHIIQSREPSLKNSNPDEIEIDFETLK PSTLRELERYVTSCLRKKRKPQAEKVDVIAGSSKMKGFSSSESESSSESSSSDSEDSETE MAPKSKKKGHPGREQKKHHHHHHQQMQQAPAPVPQQPPPPPQQPPPPPPPQQQQQPPPPP PPPSMPQQAAPAMKSSPPPFIATQVPVLEPQLPGSVFDPIGHFTQPILHLPQPELPPHLP QPPEHSTPPHLNQHAVVSPPALHNALPQQPSRPSNRAAALPPKPARPPAVSPALTQTPLL PQPPMAQPPQVLLEDEEPPAPPLTSMQMQLYLQQLQKVQPPTPLLPSVKVQSQPPPPLPP PPHPSVQQQLQQQPPPPPPPQPQPPPQQQHQPPPRPVHLQPMQFSTHIQQPPPPQGQQPP HPPPGQQPPPPQPAKPQQVIQHHHSPRHHKSDPYSTGHLREAPSPLMIHSPQMSQFQSLT HQSPPQQNVQPKKQELRAASVVQPQPLVVVKEEKIHSPIIRSEPFSPSLRPEPPKHPESI KAPVHLPQRPEMKPVDVGRPVIRPPEQNAPPPGAPDKDKQKQEPKTPVAPKKDLKIKNMG SWASLVQKHPTTPSSTAKSSSDSFEQFRRAAREKEEREKALKAQAEHAEKEKERLRQERM RSREDEDALEQARRAHEEARRRQEQQQQQRQEQQQQQQQQAAAVAAAATPQAQSSQPQSM LDQQRELARKREQERRRREAMAATIDMNFQSDLLSIFEENLF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T95EMP | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 9 Clinical Trial Drugs | + | ||||
| 1 | CPI-0610 | Drug Info | Phase 3 | Myelofibrosis | [2] | |
| 2 | INCB57643 | Drug Info | Phase 1/2 | Advanced malignancy | [3] | |
| 3 | OTX-015 | Drug Info | Phase 1/2 | Acute myeloid leukaemia | [4] | |
| 4 | PLX2853 | Drug Info | Phase 1/2 | Acute myeloid leukaemia | [5] | |
| 5 | RVX-208 | Drug Info | Phase 1/2 | Alzheimer disease | [6], [7] | |
| 6 | ABBV-744 | Drug Info | Phase 1 | Prostate cancer | [3] | |
| 7 | AZD5153 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
| 8 | GSK525762 | Drug Info | Phase 1 | Solid tumour/cancer | [9], [10], [11], [12] | |
| 9 | TEN010 | Drug Info | Phase 1 | Advanced solid tumour | [13] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 5 Modulator drugs | + | ||||
| 1 | CPI-0610 | Drug Info | [1], [10], [11], [14] | |||
| 2 | OTX-015 | Drug Info | [1], [15], [16] | |||
| 3 | RVX-208 | Drug Info | [1], [17] | |||
| 4 | GSK525762 | Drug Info | [1], [14] | |||
| 5 | TEN010 | Drug Info | [1] | |||
| Inhibitor | [+] 48 Inhibitor drugs | + | ||||
| 1 | INCB57643 | Drug Info | [3] | |||
| 2 | PLX2853 | Drug Info | [3] | |||
| 3 | ABBV-744 | Drug Info | [3] | |||
| 4 | AZD5153 | Drug Info | [3] | |||
| 5 | Aminocyclopentenone compound 1 | Drug Info | [18] | |||
| 6 | Aminocyclopentenone compound 2 | Drug Info | [18] | |||
| 7 | Aminocyclopentenone compound 3 | Drug Info | [18] | |||
| 8 | Aminocyclopentenone compound 4 | Drug Info | [18] | |||
| 9 | Aminocyclopentenone compound 5 | Drug Info | [18] | |||
| 10 | Aminocyclopentenone compound 6 | Drug Info | [18] | |||
| 11 | Benzothiazepine analog 11 | Drug Info | [18] | |||
| 12 | Benzothiazepine analog 12 | Drug Info | [18] | |||
| 13 | PMID26924192-Compound-102 | Drug Info | [18] | |||
| 14 | PMID26924192-Compound-103 | Drug Info | [18] | |||
| 15 | PMID26924192-Compound-104 | Drug Info | [18] | |||
| 16 | PMID26924192-Compound-105 | Drug Info | [18] | |||
| 17 | PMID26924192-Compound-20 | Drug Info | [18] | |||
| 18 | PMID26924192-Compound-22 | Drug Info | [18] | |||
| 19 | PMID26924192-Compound-23 | Drug Info | [18] | |||
| 20 | PMID26924192-Compound-24 | Drug Info | [18] | |||
| 21 | PMID26924192-Compound-25 | Drug Info | [18] | |||
| 22 | PMID26924192-Compound-30 | Drug Info | [18] | |||
| 23 | PMID26924192-Compound-31 | Drug Info | [18] | |||
| 24 | PMID26924192-Compound-32 | Drug Info | [18] | |||
| 25 | Pyrazole and thiophene derivative 1 | Drug Info | [18] | |||
| 26 | Pyrazole and thiophene derivative 2 | Drug Info | [18] | |||
| 27 | Pyrazole and thiophene derivative 3 | Drug Info | [18] | |||
| 28 | Pyrazole and thiophene derivative 4 | Drug Info | [18] | |||
| 29 | Pyrrolo-pyrrolone derivative 2 | Drug Info | [18] | |||
| 30 | Pyrrolo-pyrrolone derivative 3 | Drug Info | [18] | |||
| 31 | Pyrrolo-pyrrolone derivative 4 | Drug Info | [18] | |||
| 32 | BzT-7 | Drug Info | [19] | |||
| 33 | CPI-203 | Drug Info | [20] | |||
| 34 | GW841819X | Drug Info | [21] | |||
| 35 | isoxazole azepine compound 3 | Drug Info | [22] | |||
| 36 | MS417 | Drug Info | [23] | |||
| 37 | MS436 | Drug Info | [24] | |||
| 38 | PFI-1 | Drug Info | [25] | |||
| 39 | PMID21851057C4d | Drug Info | [26] | |||
| 40 | PMID23517011C9 | Drug Info | [27] | |||
| 41 | PMID24000170C36 | Drug Info | [28] | |||
| 42 | PMID24000170C38 | Drug Info | [28] | |||
| 43 | PMID25408830C1 | Drug Info | [29] | |||
| 44 | PMID25408830C2 | Drug Info | [29] | |||
| 45 | PMID25408830C3 | Drug Info | [29] | |||
| 46 | PMID25703523C7d | Drug Info | [30] | |||
| 47 | XD1 | Drug Info | [31] | |||
| 48 | XD14 | Drug Info | [31] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Colchicine | Ligand Info | |||||
| Structure Description | Joint nentron and X-ray structure of BRD4 in complex with colchicin | PDB:6AJZ | ||||
| Method | X-ray diffraction | Resolution | 1.30 Å | Mutation | No | [32] |
| PDB Sequence |
MHHHHHHMST
43 NPPPPETSNP53 NKPKRQTNQL63 QYLLRVVLKT73 LWKHQFAWPF83 QQPVDAVKLN 93 LPDYYKIIKT103 PMDMGTIKKR113 LENNYYWNAQ123 ECIQDFNTMF133 TNCYIYNKPG 143 DDIVLMAEAL153 EKLFLQKINE163 LPT
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Fedratinib | Ligand Info | |||||
| Structure Description | Crystal structure of the first bromodomain of human BRD4 in complex with TG101348 | PDB:4PS5 | ||||
| Method | X-ray diffraction | Resolution | 1.40 Å | Mutation | No | [33] |
| PDB Sequence |
SMNPPPPETS
51 NPNKPKRQTN61 QLQYLLRVVL71 KTLWKHQFAW81 PFQQPVDAVK91 LNLPDYYKII 101 KTPMDMGTIK111 KRLENNYYWN121 AQECIQDFNT131 MFTNCYIYNK141 PGDDIVLMAE 151 ALEKLFLQKI161 NELPTEE
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Uncharacterized protein KIAA2026 (KIAA2026) | 24.603 (31/126) | 6.34E-06 | |
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 15 | Degree centrality | 1.61E-03 | Betweenness centrality | 5.67E-03 |
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| Closeness centrality | 2.40E-01 | Radiality | 1.42E+01 | Clustering coefficient | 3.81E-02 |
| Neighborhood connectivity | 3.84E+01 | Topological coefficient | 8.08E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Chemical Compounds to monitor Proteins | |||||
| References | Top | |||||
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| REF 1 | Targeting bromodomains: epigenetic readers of lysine acetylation.Nat Rev Drug Discov.2014 May;13(5):337-56. | |||||
| REF 2 | ClinicalTrials.gov (NCT04603495) Study of CPI-0610 in Myelofibrosis (MF) (MANIFEST-2). U.S. National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | ClinicalTrials.gov (NCT02303782) A Study Assessing tOTX015 in Combination With Azacitidine (AZA) or AZA Single Agent in Patients With Newly-diagnosed Acute Myeloid Leukemia (AML) Not Candidate for Standard Intensive Induction Therapy (SIIT). U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04493619) PLX2853 as a Single Agent in Advanced Gynecological Malignancies and in Combination With Carboplatin in Platinum-Resistant Epithelial Ovarian Cancer. U.S. National Institutes of Health. | |||||
| REF 6 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7034). | |||||
| REF 7 | ClinicalTrials.gov (NCT00768274) Safety, Pharmacokinetic Study of RVX000222 in Healthy Subjects and Subjects With Low HDL Cholesterol. U.S. National Institutes of Health. | |||||
| REF 8 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 9 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7033). | |||||
| REF 10 | Selective inhibition of BET bromodomains. Nature. 2010 Dec 23;468(7327):1067-73. | |||||
| REF 11 | Suppression of inflammation by a synthetic histone mimic. Nature. 2010 Dec 23;468(7327):1119-23. | |||||
| REF 12 | Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.Nat Rev Drug Discov. 2016 Aug;15(8):533-50. | |||||
| REF 13 | ClinicalTrials.gov (NCT02308761) A Dose Escalation and Cohort Expansion Study of TEN-010 in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndrome. U.S. National Institutes of Health. | |||||
| REF 14 | BET inhibitor resistance emerges from leukaemia stem cells.Nature.2015 Sep 24;525(7570):538-42. | |||||
| REF 15 | BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015 Jul 10;6(19):17698-712. | |||||
| REF 16 | The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs.Clin Cancer Res.2015 Apr 1;21(7):1628-38. | |||||
| REF 17 | RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist.PLoS One.2013 Dec 31;8(12):e83190. | |||||
| REF 18 | BET inhibitors in cancer therapeutics: a patent review.Expert Opin Ther Pat. 2016;26(4):505-22. | |||||
| REF 19 | Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg Med Chem. 2012 Mar 15;20(6):1878-86. | |||||
| REF 20 | BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc Natl Acad Sci U S A. 2012 May 1;109(18):6927-32. | |||||
| REF 21 | Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 2011 Jun 9;54(11):3827-38. | |||||
| REF 22 | Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors. ACS Med Chem Lett. 2013 Jul 16;4(9):835-40. | |||||
| REF 23 | Down-regulation of NF- B transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem. 2012 Aug 17;287(34):28840-51. | |||||
| REF 24 | Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains. J Med Chem. 2013 Nov 27;56(22):9251-64. | |||||
| REF 25 | Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J Med Chem. 2012 Nov 26;55(22):9831-7. | |||||
| REF 26 | 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J Med Chem. 2011 Oct 13;54(19):6761-70. | |||||
| REF 27 | Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands. J Med Chem. 2013 Apr 25;56(8):3217-27. | |||||
| REF 28 | Naphthyridines as novel BET family bromodomain inhibitors. ChemMedChem. 2014 Mar;9(3):580-9. | |||||
| REF 29 | 1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain. ACS Med Chem Lett. 2014 Sep 10;5(11):1190-5. | |||||
| REF 30 | 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain. J Med Chem. 2015 Mar 26;58(6):2718-36. | |||||
| REF 31 | 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew Chem Int Ed Engl. 2013 Dec 23;52(52):14055-9. | |||||
| REF 32 | Structural and thermodynamic characterization of the binding of isoliquiritigenin to the first bromodomain of BRD4. FEBS J. 2019 May;286(9):1656-1667. | |||||
| REF 33 | Acetyl-lysine binding site of bromodomain-containing protein 4 (BRD4) interacts with diverse kinase inhibitors. ACS Chem Biol. 2014 May 16;9(5):1160-71. | |||||
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