Target Information
| Target General Information | Top | |||||
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| Target ID |
T46365
(Former ID: TTDR00116)
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| Target Name |
M-phase inducer phosphatase 2 (MPIP2)
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| Synonyms |
Dual specificity phosphatase Cdc25B; Cdc25B phosphatase; CDC25HU2
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| Gene Name |
CDC25B
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Lung cancer [ICD-11: 2C25] | |||||
| Function |
Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Directly dephosphorylates CDK1 and stimulates its kinase activity. The three isoforms seem to have a different level of activity. Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression.
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| BioChemical Class |
Phosphoric monoester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.3.48
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| Sequence |
MEVPQPEPAPGSALSPAGVCGGAQRPGHLPGLLLGSHGLLGSPVRAAASSPVTTLTQTMH
DLAGLGSETPKSQVGTLLFRSRSRLTHLSLSRRASESSLSSESSESSDAGLCMDSPSPMD PHMAEQTFEQAIQAASRIIRNEQFAIRRFQSMPVRLLGHSPVLRNITNSQAPDGRRKSEA GSGAASSSGEDKENDGFVFKMPWKPTHPSSTHALAEWASRREAFAQRPSSAPDLMCLSPD RKMEVEELSPLALGRFSLTPAEGDTEEDDGFVDILESDLKDDDAVPPGMESLISAPLVKT LEKEEEKDLVMYSKCQRLFRSPSMPCSVIRPILKRLERPQDRDTPVQNKRRRSVTPPEEQ QEAEEPKARVLRSKSLCHDEIENLLDSDHRELIGDYSKAFLLQTVDGKHQDLKYISPETM VALLTGKFSNIVDKFVIVDCRYPYEYEGGHIKTAVNLPLERDAESFLLKSPIAPCSLDKR VILIFHCEFSSERGPRMCRFIRERDRAVNDYPSLYYPEMYILKGGYKEFFPQHPNFCEPQ DYRPMNHEAFKDELKTFRLKTRSWAGERSRRELCSRLQDQ Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T10AWW | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Avastin+/-Tarceva | Drug Info | Phase 3 | Non-small-cell lung cancer | [2] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | MX-7065 | Drug Info | Terminated | Solid tumour/cancer | [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 15 Inhibitor drugs | + | ||||
| 1 | Avastin+/-Tarceva | Drug Info | [1] | |||
| 2 | MX-7065 | Drug Info | [4] | |||
| 3 | 2-Sulfhydryl-Ethanol | Drug Info | [5] | |||
| 4 | 3-isopropyl-4-(phenylthio)naphthalene-1,2-dione | Drug Info | [6] | |||
| 5 | 3-isopropyl-4-phenylnaphthalene-1,2-dione | Drug Info | [6] | |||
| 6 | 4-(p-toluidino)-3-isopropylnaphthalene-1,2-dione | Drug Info | [6] | |||
| 7 | 4-ethoxynaphthalene-1,2-dione | Drug Info | [1] | |||
| 8 | 5,6,7,8-tetrahydroanthracene-1,4-dione | Drug Info | [1] | |||
| 9 | 6,7-dibromoquinoline-5,8-dione | Drug Info | [7] | |||
| 10 | ADOCIAQUINONE B | Drug Info | [7] | |||
| 11 | ANTHRAQUINONE | Drug Info | [1] | |||
| 12 | Cysteinesulfonic Acid | Drug Info | [5] | |||
| 13 | Double Oxidized Cysteine | Drug Info | [5] | |||
| 14 | Methyl Mercury Ion | Drug Info | [5] | |||
| 15 | NSC-95397 | Drug Info | [7] | |||
| 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: Tungstate | Ligand Info | |||||
| Structure Description | HUMAN CDC25B CATALYTIC DOMAIN WITH TUNGSTATE | PDB:1CWS | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [8] |
| PDB Sequence |
SDHRELIGDY
382 SKAFLLQTVD392 GKHQDLKYIS402 PETMVALLTG412 KFSNIVDKFV422 IVDCRYPYEY 432 EGGHIKTAVN442 LPLERDAESF452 LLKSPIAPCS462 LDKRVILIFH472 CEFSSERGPR 482 MCRFIRERDR492 AVNDYPSLYY502 PEMYILKGGY512 KEFFPQHPNF522 CEPQDYRPMN 532 HEAFKDELKT542 FRLKTRSWA
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| Ligand Name: 2-[(2-Cyano-3-Fluoro-5-Hydroxyphenyl)sulfanyl]ethanesulfonic Acid | Ligand Info | |||||
| Structure Description | Structure of the CDC25B Phosphatase Catalytic Domain with Bound Inhibitor | PDB:4WH9 | ||||
| Method | X-ray diffraction | Resolution | 1.50 Å | Mutation | Yes | [9] |
| PDB Sequence |
HRELIGDYSK
384 AFLLQTVDGK394 HQDLKYISPE404 TMVALLTGKF414 SNIVDKFVIV424 DCRYPYEYEG 434 GHIKTAVNLP444 LERDAESFLL454 KSPIAPCSLD464 KRVILIFHSE474 FSSERGPRMC 484 RFIRERDRAV494 NDYPSLYYPE504 MYILKGGYKE514 FFPQHPNFCE524 PQDYRPMNHE 534 AFKDELKTFR544 LKTRSWA
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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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There is no similarity protein (E value < 0.005) for this target
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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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| MAPK signaling pathway | hsa04010 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Cell cycle | hsa04110 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Progesterone-mediated oocyte maturation | hsa04914 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Degree | 18 | Degree centrality | 1.93E-03 | Betweenness centrality | 1.82E-04 |
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| Closeness centrality | 2.32E-01 | Radiality | 1.41E+01 | Clustering coefficient | 2.94E-01 |
| Neighborhood connectivity | 5.16E+01 | Topological coefficient | 1.33E-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-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | MAPK signaling pathway | |||||
| 2 | Cell cycle | |||||
| 3 | Progesterone-mediated oocyte maturation | |||||
| 4 | MicroRNAs in cancer | |||||
| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| 2 | TGF_beta_Receptor Signaling Pathway | |||||
| 3 | Wnt Signaling Pathway | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | PLK1 signaling events | |||||
| 2 | FOXM1 transcription factor network | |||||
| 3 | p38 signaling mediated by MAPKAP kinases | |||||
| 4 | Aurora A signaling | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Cyclin B2 mediated events | |||||
| 2 | Cyclin A/B1 associated events during G2/M transition | |||||
| 3 | Cyclin A:Cdk2-associated events at S phase entry | |||||
| WikiPathways | [+] 8 WikiPathways | + | ||||
| 1 | Senescence and Autophagy in Cancer | |||||
| 2 | MAPK Signaling Pathway | |||||
| 3 | Retinoblastoma (RB) in Cancer | |||||
| 4 | Prostate Cancer | |||||
| 5 | Integrated Breast Cancer Pathway | |||||
| 6 | Integrated Cancer pathway | |||||
| 7 | Mitotic G2-G2/M phases | |||||
| 8 | Cell Cycle | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Bioactivities of simplified adociaquinone B and naphthoquinone derivatives against Cdc25B, MKP-1, and MKP-3 phosphatases. Bioorg Med Chem. 2009 Mar 15;17(6):2276-81. | |||||
| REF 2 | Clinical pipeline report, company report or official report of Roche. | |||||
| REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016615) | |||||
| REF 4 | Handbook of Assay Development in Drug Discovery, Lisa K. Minor, 2013. Page(11). | |||||
| REF 5 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 6 | Synthesis of miltirone analogues as inhibitors of Cdc25 phosphatases. Bioorg Med Chem Lett. 2006 Apr 1;16(7):1905-8. | |||||
| REF 7 | Novel naphthoquinone and quinolinedione inhibitors of CDC25 phosphatase activity with antiproliferative properties. Bioorg Med Chem. 2008 Oct 1;16(19):9040-9. | |||||
| REF 8 | Crystal structure of the catalytic subunit of Cdc25B required for G2/M phase transition of the cell cycle. J Mol Biol. 1999 Oct 29;293(3):559-68. | |||||
| REF 9 | Inhibition of CDC25B phosphatase through disruption of protein-protein interaction. ACS Chem Biol. 2015 Feb 20;10(2):390-4. | |||||
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