Target Information
Target General Information | Top | |||||
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Target ID |
T36741
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Target Name |
p53-binding protein Mdm4 (MDM4)
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Synonyms |
Protein Mdmx; Mdm2-like p53-binding protein; Double minute 4 protein
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Gene Name |
MDM4
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 4 Target-related Diseases | + | ||||
1 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
2 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
3 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
4 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
Function |
Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.
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BioChemical Class |
MDM2/MDM4 family
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UniProt ID | ||||||
Sequence |
MTSFSTSAQCSTSDSACRISPGQINQVRPKLPLLKILHAAGAQGEMFTVKEVMHYLGQYI
MVKQLYDQQEQHMVYCGGDLLGELLGRQSFSVKDPSPLYDMLRKNLVTLATATTDAAQTL ALAQDHSMDIPSQDQLKQSAEESSTSRKRTTEDDIPTLPTSEHKCIHSREDEDLIENLAQ DETSRLDLGFEEWDVAGLPWWFLGNLRSNYTPRSNGSTDLQTNQDVGTAIVSDTTDDLWF LNESVSEQLGVGIKVEAADTEQTSEEVGKVSDKKVIEVGKNDDLEDSKSLSDDTDVEVTS EDEWQCTECKKFNSPSKRYCFRCWALRKDWYSDCSKLTHSLSTSDITAIPEKENEGNDVP DCRRTISAPVVRPKDAYIKKENSKLFDPCNSVEFLDLAHSSESQETISSMGEQLDNLSEQ RTDTENMEDCQNLLKPCSLCEKRPRDGNIIHGRTGHLVTCFHCARRLKKAGASCPICKKE IQLVIKVFIA Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T03H54 |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
1 | ALRN-6924 | Drug Info | Phase 2 | Haematological malignancy | [2] | |
Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
1 | NSC-207895 | Drug Info | Preclinical | Solid tumour/cancer | [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 2 Inhibitor drugs | + | ||||
1 | ALRN-6924 | Drug Info | [1] | |||
2 | NSC-207895 | Drug Info | [3] |
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: 7-methoxy-~{N}-[(3~{S})-1-(4-methylphenyl)pyrrolidin-3-yl]-1~{H}-indole-3-carboxamide | Ligand Info | |||||
Structure Description | HDMX (14-111; C17S) COMPLEXED WITH COMPOUND 16 AT 1.20A; Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes | PDB:6Q9Y | ||||
Method | X-ray diffraction | Resolution | 1.20 Å | Mutation | Yes | [4] |
PDB Sequence |
QVRPKLPLLK
36 ILHAAGAQGE46 MFTVKEVMHY56 LGQYIMVKQL66 YDQQEQHMVY76 CGGDLLGELL 86 GRQSFSVKDP96 SPLYDMLRKN106 LVTLA
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Ligand Name: (4~{S})-4-(4-chlorophenyl)-5-[(1~{S})-1-(3-chlorophenyl)ethyl]-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-d]imidazol-6-one | Ligand Info | |||||
Structure Description | X-ray structure of compound 15 bound to HdmX: Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes | PDB:6Q9W | ||||
Method | X-ray diffraction | Resolution | 1.55 Å | Mutation | Yes | [4] |
PDB Sequence |
NQVRPKLPLL
35 KILHAAGAQG45 EMFTVKEVMH55 YLGQYIMVKQ65 LYDQQEQHMV75 YCGGDLLGEL 85 LGRQSFSVKD95 PSPLYDMLRK105 NLVTLA
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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).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
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
Human Pathway Affiliation
Biological Network Descriptors
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Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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Peroxisome assembly protein 12 (PEX12) | 24.528 (39/159) | 1.00E-03 |
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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KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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p53 signaling pathway | hsa04115 | Affiliated Target |
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Class: Cellular Processes => Cell growth and death | Pathway Hierarchy |
Degree | 12 | Degree centrality | 1.29E-03 | Betweenness centrality | 9.88E-05 |
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Closeness centrality | 2.44E-01 | Radiality | 1.43E+01 | Clustering coefficient | 3.64E-01 |
Neighborhood connectivity | 7.07E+01 | Topological coefficient | 1.26E-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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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 Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
1 | p53 signaling pathway | |||||
2 | MicroRNAs in cancer |
References | Top | |||||
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REF 1 | Anti-ageing pipeline starts to mature.Nat Rev Drug Discov. 2018 Sep;17(9):609-612. | |||||
REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 3 | Emerging therapies targeting the ubiquitin proteasome system in cancer. J Clin Invest. 2014 Jan;124(1):6-12. | |||||
REF 4 | Structural States of Hdm2 and HdmX: X-ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes. ChemMedChem. 2019 Jul 17;14(14):1305-1314. |
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