Target Information
| Target General Information | Top | |||||
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| Target ID |
T90985
(Former ID: TTDI02033)
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| Target Name |
Bromodomain testis-specific protein (BRDT)
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| Synonyms |
Cancer/testis antigen 9; CT9
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| Gene Name |
BRDT
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Testicular cancer [ICD-11: 2C80] | |||||
| Function |
Required in late pachytene spermatocytes: plays a role in meiotic and post-meiotic cells by binding to acetylated histones at the promoter of specific meiotic and post-meiotic genes, facilitating their activation at the appropriate time. In the post-meiotic phase of spermatogenesis, binds to hyperacetylated histones and participates in their general removal from DNA. Also recognizes and binds a subset of butyrylated histones: able to bind histone H4 butyrylated at 'Lys-8' (H4K8ac), while it is not able to bind H4 butyrylated at 'Lys-5' (H4K5ac). Also acts as a component of the splicing machinery in pachytene spermatocytes and round spermatids and participates in 3'-UTR truncation of specific mRNAs in post-meiotic spermatids. Required for chromocenter organization, a structure comprised of peri-centromeric heterochromatin. Testis-specific chromatin protein that specifically binds histone H4 acetylated at 'Lys-5' and 'Lys-8' (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis.
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| BioChemical Class |
Bromodomain
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| UniProt ID | ||||||
| Sequence |
MSLPSRQTAIIVNPPPPEYINTKKNGRLTNQLQYLQKVVLKDLWKHSFSWPFQRPVDAVK
LQLPDYYTIIKNPMDLNTIKKRLENKYYAKASECIEDFNTMFSNCYLYNKPGDDIVLMAQ ALEKLFMQKLSQMPQEEQVVGVKERIKKGTQQNIAVSSAKEKSSPSATEKVFKQQEIPSV FPKTSISPLNVVQGASVNSSSQTAAQVTKGVKRKADTTTPATSAVKASSEFSPTFTEKSV ALPPIKENMPKNVLPDSQQQYNVVKTVKVTEQLRHCSEILKEMLAKKHFSYAWPFYNPVD VNALGLHNYYDVVKNPMDLGTIKEKMDNQEYKDAYKFAADVRLMFMNCYKYNPPDHEVVT MARMLQDVFETHFSKIPIEPVESMPLCYIKTDITETTGRENTNEASSEGNSSDDSEDERV KRLAKLQEQLKAVHQQLQVLSQVPFRKLNKKKEKSKKEKKKEKVNNSNENPRKMCEQMRL KEKSKRNQPKKRKQQFIGLKSEDEDNAKPMNYDEKRQLSLNINKLPGDKLGRVVHIIQSR EPSLSNSNPDEIEIDFETLKASTLRELEKYVSACLRKRPLKPPAKKIMMSKEELHSQKKQ ELEKRLLDVNNQLNSRKRQTKSDKTQPSKAVENVSRLSESSSSSSSSSESESSSSDLSSS DSSDSESEMFPKFTEVKPNDSPSKENVKKMKNECIPPEGRTGVTQIGYCVQDTTSANTTL VHQTTPSHVMPPNHHQLAFNYQELEHLQTVKNISPLQILPPSGDSEQLSNGITVMHPSGD SDTTMLESECQAPVQKDIKIKNADSWKSLGKPVKPSGVMKSSDELFNQFRKAAIEKEVKA RTQELIRKHLEQNTKELKASQENQRDLGNGLTVESFSNKIQNKCSGEEQKEHQQSSEAQD KSKLWLLKDRDLARQKEQERRRREAMVGTIDMTLQSDIMTMFENNFD 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 | (+)-JQ1 | Drug Info | Phase 1 | Testicular cancer | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 6 Inhibitor drugs | + | ||||
| 1 | (+)-JQ1 | Drug Info | [1] | |||
| 2 | PMID26924192-Compound-102 | Drug Info | [3] | |||
| 3 | PMID26924192-Compound-103 | Drug Info | [3] | |||
| 4 | PMID26924192-Compound-104 | Drug Info | [3] | |||
| 5 | PMID26924192-Compound-105 | Drug Info | [3] | |||
| 6 | XD14 | Drug Info | [4] | |||
| 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: Volasertib | Ligand Info | |||||
| Structure Description | Crystal structure of the second bromodomain (BD2) of human BRDT bound to Volasertib | PDB:7LEJ | ||||
| Method | X-ray diffraction | Resolution | 1.73 Å | Mutation | No | [5] |
| PDB Sequence |
AAYFQGAAST
266 VKVTEQLRHC276 SEILKEMLAK286 KHFSYAWPFY296 NPVDVNALGL306 HNYYDVVKNP 316 MDLGTIKEKM326 DNQEYKDAYK336 FAADVRLMFM346 NCYKYNPPDH356 EVVTMARMLQ 366 DVFETHFSKI376 P
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: BI 2536 | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRDT IN COMPLEX WITH BI2536 | PDB:5VBQ | ||||
| Method | X-ray diffraction | Resolution | 1.65 Å | Mutation | No | [5] |
| PDB Sequence |
GAASTNQLQY
34 LQKVVLKDLW44 KHSFSWPFQR54 PVDAVKLQLP64 DYYTIIKNPM74 DLNTIKKRLE 84 NKYYAKASEC94 IEDFNTMFSN104 CYLYNKPGDD114 IVLMAQALEK124 LFMQKLSQMP 134 QE
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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) | 24.786 (29/117) | 3.36E-04 | |
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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 | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 2.36E-06 |
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| Closeness centrality | 1.94E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 3.75E+01 | Topological coefficient | 5.00E-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 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 | Small-molecule inhibition of BRDT for male contraception. Cell. 2012 Aug 17;150(4):673-84. | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | BET inhibitors in cancer therapeutics: a patent review.Expert Opin Ther Pat. 2016;26(4):505-22. | |||||
| REF 4 | 4-Acyl pyrroles: mimicking acetylated lysines in histone code reading. Angew Chem Int Ed Engl. 2013 Dec 23;52(52):14055-9. | |||||
| REF 5 | Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors. J Med Chem. 2021 Nov 11;64(21):15772-15786. | |||||
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