Target Information
| Target General Information | Top | |||||
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| Target ID |
T86399
(Former ID: TTDI02030)
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| Target Name |
Bromodomain-containing protein 2 (BRD2)
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| Synonyms |
Really interesting new gene 3 protein; RING3; O27.1.1; KIAA9001
Click to Show/Hide
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| Gene Name |
BRD2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| 3 | Prostate cancer [ICD-11: 2C82] | |||||
| 4 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly. May play a role in spermatogenesis or folliculogenesis.
Click to Show/Hide
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| BioChemical Class |
Bromodomain
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| UniProt ID | ||||||
| Sequence |
MLQNVTPHNKLPGEGNAGLLGLGPEAAAPGKRIRKPSLLYEGFESPTMASVPALQLTPAN
PPPPEVSNPKKPGRVTNQLQYLHKVVMKALWKHQFAWPFRQPVDAVKLGLPDYHKIIKQP MDMGTIKRRLENNYYWAASECMQDFNTMFTNCYIYNKPTDDIVLMAQTLEKIFLQKVASM PQEEQELVVTIPKNSHKKGAKLAALQGSVTSAHQVPAVSSVSHTALYTPPPEIPTTVLNI PHPSVISSPLLKSLHSAGPPLLAVTAAPPAQPLAKKKGVKRKADTTTPTPTAILAPGSPA SPPGSLEPKAARLPPMRRESGRPIKPPRKDLPDSQQQHQSSKKGKLSEQLKHCNGILKEL LSKKHAAYAWPFYKPVDASALGLHDYHDIIKHPMDLSTVKRKMENRDYRDAQEFAADVRL MFSNCYKYNPPDHDVVAMARKLQDVFEFRYAKMPDEPLEPGPLPVSTAMPPGLAKSSSES SSEESSSESSSEEEEEEDEEDEEEEESESSDSEEERAHRLAELQEQLRAVHEQLAALSQG PISKPKRKREKKEKKKKRKAEKHRGRAGADEDDKGPRAPRPPQPKKSKKASGSGGGSAAL GPSGFGPSGGSGTKLPKKATKTAPPALPTGYDSEEEEESRPMSYDEKRQLSLDINKLPGE KLGRVVHIIQAREPSLRDSNPEEIEIDFETLKPSTLRELERYVLSCLRKKPRKPYTIKKP VGKTKEELALEKKRELEKRLQDVSGQLNSTKKPPKKANEKTESSSAQQVAVSRLSASSSS SDSSSSSSSSSSSDTSDSDSG Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | OTX-015 | Drug Info | Phase 1/2 | Acute myeloid leukaemia | [2] | |
| 2 | ABBV-744 | Drug Info | Phase 1 | Prostate cancer | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | OTX-015 | Drug Info | [1], [4], [5] | |||
| Inhibitor | [+] 16 Inhibitor drugs | + | ||||
| 1 | ABBV-744 | Drug Info | [3] | |||
| 2 | PMID26924192-Compound-102 | Drug Info | [6] | |||
| 3 | PMID26924192-Compound-103 | Drug Info | [6] | |||
| 4 | PMID26924192-Compound-104 | Drug Info | [6] | |||
| 5 | PMID26924192-Compound-105 | Drug Info | [6] | |||
| 6 | PMID26924192-Compound-106 | Drug Info | [6] | |||
| 7 | Pyrrolo-pyrrolone derivative 1 | Drug Info | [6] | |||
| 8 | BIC1 | Drug Info | [7] | |||
| 9 | ET bromodomain inhibitor | Drug Info | [8] | |||
| 10 | GW841819X | Drug Info | [9] | |||
| 11 | I-BET151 | Drug Info | [10] | |||
| 12 | ME bromodomain inhibitor | Drug Info | [8] | |||
| 13 | PMID21851057C4d | Drug Info | [11] | |||
| 14 | PMID24000170C36 | Drug Info | [12] | |||
| 15 | PMID24000170C38 | Drug Info | [12] | |||
| 16 | XD14 | Drug Info | [13] | |||
| 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: Acetaminophen | Ligand Info | |||||
| Structure Description | N-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH N-(4-hydroxyphenyl) acetamide | PDB:4A9J | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [14] |
| PDB Sequence |
VTNQLQYLHK
84 VVMKALWKHQ94 FAWPFRQPVD104 AVKLGLPDYH114 KIIKQPMDMG124 TIKRRLENNY 134 YWAASECMQD144 FNTMFTNCYI154 YNKPTDDIVL164 MAQTLEKIFL174 QKVASMPQEE 184 QE
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| Ligand Name: Volasertib | Ligand Info | |||||
| Structure Description | Crystal structure of the first bromodomain (BD1) of human BRD2 bound to volasertib | PDB:7LAK | ||||
| Method | X-ray diffraction | Resolution | 1.83 Å | Mutation | No | [15] |
| PDB Sequence |
GRVTNQLQYL
82 HKVVMKALWK92 HQFAWPFRQP102 VDAVKLGLPD112 YHKIIKQPMD122 MGTIKRRLEN 132 NYYWAASECM142 QDFNTMFTNC152 YIYNKPTDDI162 VLMAQTLEKI172 FLQKVASMPQ 182 EEQELVVTIP192
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| 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) | 25.000 (32/128) | 1.45E-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 | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 6.03E-04 |
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| Closeness centrality | 2.08E-01 | Radiality | 1.36E+01 | Clustering coefficient | 2.00E-01 |
| Neighborhood connectivity | 3.56E+01 | Topological coefficient | 2.24E-01 | Eccentricity | 12 |
| 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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| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TGF_beta_Receptor Signaling Pathway | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | Regulation of retinoblastoma protein | |||||
| 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 (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 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015 Jul 10;6(19):17698-712. | |||||
| REF 5 | 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 6 | BET inhibitors in cancer therapeutics: a patent review.Expert Opin Ther Pat. 2016;26(4):505-22. | |||||
| REF 7 | Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors. Chem Biol. 2011 Apr 22;18(4):495-507. | |||||
| REF 8 | Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science. 2014 Oct 31;346(6209):638-41. | |||||
| REF 9 | Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 2011 Jun 9;54(11):3827-38. | |||||
| REF 10 | Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011 Oct 2;478(7370):529-33. | |||||
| REF 11 | 3,5-dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J Med Chem. 2011 Oct 13;54(19):6761-70. | |||||
| REF 12 | Naphthyridines as novel BET family bromodomain inhibitors. ChemMedChem. 2014 Mar;9(3):580-9. | |||||
| REF 13 | 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew Chem Int Ed Engl. 2013 Dec 23;52(52):14055-9. | |||||
| REF 14 | Fragment-based discovery of bromodomain inhibitors part 1: inhibitor binding modes and implications for lead discovery. J Med Chem. 2012 Jan 26;55(2):576-86. | |||||
| REF 15 | Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors. J Med Chem. 2021 Nov 11;64(21):15772-15786. | |||||
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