Target Information
| Target General Information | Top | |||||
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| Target ID |
T42048
(Former ID: TTDI02031)
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| Target Name |
Bromodomain-containing protein 3 (BRD3)
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| Synonyms |
RING3like protein; RING3L; RING3-like protein; KIAA0043
Click to Show/Hide
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| Gene Name |
BRD3
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Prostate cancer [ICD-11: 2C82] | |||||
| Function |
Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets. Chromatin reader that recognizes and binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors.
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| BioChemical Class |
Bromodomain
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| UniProt ID | ||||||
| Sequence |
MSTATTVAPAGIPATPGPVNPPPPEVSNPSKPGRKTNQLQYMQNVVVKTLWKHQFAWPFY
QPVDAIKLNLPDYHKIIKNPMDMGTIKKRLENNYYWSASECMQDFNTMFTNCYIYNKPTD DIVLMAQALEKIFLQKVAQMPQEEVELLPPAPKGKGRKPAAGAQSAGTQQVAAVSSVSPA TPFQSVPPTVSQTPVIAATPVPTITANVTSVPVPPAAAPPPPATPIVPVVPPTPPVVKKK GVKRKADTTTPTTSAITASRSESPPPLSDPKQAKVVARRESGGRPIKPPKKDLEDGEVPQ HAGKKGKLSEHLRYCDSILREMLSKKHAAYAWPFYKPVDAEALELHDYHDIIKHPMDLST VKRKMDGREYPDAQGFAADVRLMFSNCYKYNPPDHEVVAMARKLQDVFEMRFAKMPDEPV EAPALPAPAAPMVSKGAESSRSSEESSSDSGSSDSEEERATRLAELQEQLKAVHEQLAAL SQAPVNKPKKKKEKKEKEKKKKDKEKEKEKHKVKAEEEKKAKVAPPAKQAQQKKAPAKKA NSTTTAGRQLKKGGKQASASYDSEEEEEGLPMSYDEKRQLSLDINRLPGEKLGRVVHIIQ SREPSLRDSNPDEIEIDFETLKPTTLRELERYVKSCLQKKQRKPFSASGKKQAAKSKEEL AQEKKKELEKRLQDVSGQLSSSKKPARKEKPGSAPSGGPSRLSSSSSSESGSSSSSGSSS DSSDSE 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) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | ABBV-744 | Drug Info | Phase 1 | Prostate cancer | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | ABBV-744 | Drug Info | [1] | |||
| 2 | PMID26924192-Compound-102 | Drug Info | [2] | |||
| 3 | PMID26924192-Compound-103 | Drug Info | [2] | |||
| 4 | PMID26924192-Compound-104 | Drug Info | [2] | |||
| 5 | PMID26924192-Compound-105 | Drug Info | [2] | |||
| 6 | Pyrrolo-pyrrolone derivative 1 | Drug Info | [2] | |||
| 7 | GW841819X | Drug Info | [3] | |||
| 8 | I-BET151 | Drug Info | [4] | |||
| 9 | PMID24000170C36 | Drug Info | [5] | |||
| 10 | PMID24000170C38 | Drug Info | [5] | |||
| 11 | XD14 | Drug Info | [6] | |||
| 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: BI 2536 | Ligand Info | |||||
| Structure Description | Crystal structure of the second bromodomain (BD2) of human BRD3 bound to BI2536 | PDB:7L9L | ||||
| Method | X-ray diffraction | Resolution | 1.55 Å | Mutation | No | [7] |
| PDB Sequence |
SMGKLSEHLR
313 YCDSILREML323 SKKHAAYAWP333 FYKPVDAEAL343 ELHDYHDIIK353 HPMDLSTVKR 363 KMDGREYPDA373 QGFAADVRLM383 FSNCYKYNPP393 DHEVVAMARK403 LQDVFEMRFA 413 KMP
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| Ligand Name: Ro5203280 | Ligand Info | |||||
| Structure Description | Crystal structure of the second bromodomain (BD2) of human BRD3 bound to Ro3280 | PDB:7L72 | ||||
| Method | X-ray diffraction | Resolution | 1.50 Å | Mutation | No | [7] |
| PDB Sequence |
SMGKLSEHLR
313 YCDSILREML323 SKKHAAYAWP333 FYKPVDAEAL343 ELHDYHDIIK353 HPMDLSTVKR 363 KMDGREYPDA373 QGFAADVRLM383 FSNCYKYNPP393 DHEVVAMARK403 LQDVFEMRFA 413 KMP
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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) | 20.800 (52/250) | 6.14E-08 | |
| Otogelin (OTOG) | 24.211 (46/190) | 5.00E-03 | |
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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 | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.85E-01 | Radiality | 1.31E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.90E+01 | Topological coefficient | 1.00E+00 | 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-regulating microRNAs | ||||||
| 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 | IL2 Signaling Pathway | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Chemical Compounds to monitor Proteins | |||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | BET inhibitors in cancer therapeutics: a patent review.Expert Opin Ther Pat. 2016;26(4):505-22. | |||||
| REF 3 | Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J Med Chem. 2011 Jun 9;54(11):3827-38. | |||||
| REF 4 | Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011 Oct 2;478(7370):529-33. | |||||
| REF 5 | Naphthyridines as novel BET family bromodomain inhibitors. ChemMedChem. 2014 Mar;9(3):580-9. | |||||
| REF 6 | 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew Chem Int Ed Engl. 2013 Dec 23;52(52):14055-9. | |||||
| REF 7 | Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors. J Med Chem. 2021 Nov 11;64(21):15772-15786. | |||||
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