Target Information
| Target General Information | Top | |||||
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| Target ID |
T69991
(Former ID: TTDC00256)
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| Target Name |
Wee1-like protein kinase (WEE1)
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| Synonyms |
Wee1A kinase; WEE1hu
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| Gene Name |
WEE1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Ovarian cancer [ICD-11: 2C73] | |||||
| 2 | Uterine ligament/parametrium/uterine adnexa neoplasm [ICD-11: 2C72] | |||||
| 3 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation. Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.2
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| Sequence |
MSFLSRQQPPPPRRAGAACTLRQKLIFSPCSDCEEEEEEEEEEGSGHSTGEDSAFQEPDS
PLPPARSPTEPGPERRRSPGPAPGSPGELEEDLLLPGACPGADEAGGGAEGDSWEEEGFG SSSPVKSPAAPYFLGSSFSPVRCGGPGDASPRGCGARRAGEGRRSPRPDHPGTPPHKTFR KLRLFDTPHTPKSLLSKARGIDSSSVKLRGSSLFMDTEKSGKREFDVRQTPQVNINPFTP DSLLLHSSGQCRRRKRTYWNDSCGEDMEASDYELEDETRPAKRITITESNMKSRYTTEFH ELEKIGSGEFGSVFKCVKRLDGCIYAIKRSKKPLAGSVDEQNALREVYAHAVLGQHSHVV RYFSAWAEDDHMLIQNEYCNGGSLADAISENYRIMSYFKEAELKDLLLQVGRGLRYIHSM SLVHMDIKPSNIFISRTSIPNAASEEGDEDDWASNKVMFKIGDLGHVTRISSPQVEEGDS RFLANEVLQENYTHLPKADIFALALTVVCAAGAEPLPRNGDQWHEIRQGRLPRIPQVLSQ EFTELLKVMIHPDPERRPSAMALVKHSVLLSASRKSAEQLRIELNAEKFKNSLLQKELKK AQMAKAAAEERALFTDRMATRSTTQSNRTSRLIGKKMNRSVSLTIY Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T37VTM | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | MK-1775 | Drug Info | Phase 2 | Ovarian cancer | [2], [3] | |
| 2 | ZN-c3 | Drug Info | Phase 2 | Uterine serous carcinoma | [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | MK-1775 | Drug Info | [1], [5] | |||
| 2 | ZN-c3 | Drug Info | [6] | |||
| 3 | 9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione | 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: Bosutinib | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF HUMAN WEE1 KINASE DOMAIN IN COMPLEX WITH BOSUTINIB | PDB:5VC3 | ||||
| Method | X-ray diffraction | Resolution | 1.97 Å | Mutation | No | [8] |
| PDB Sequence |
SRYTTEFHEL
302 EKIGSGEFGS312 VFKCVKRLDG322 CIYAIKRSKK332 PLAGSVDEQN342 ALREVYAHAV 352 LGQHSHVVRY362 FSAWAEDDHM372 LIQNEYCNGG382 SLADAISENY392 RIMSYFKEAE 402 LKDLLLQVGR412 GLRYIHSMSL422 VHMDIKPSNI432 FISRTKVMFK460 IGDLGHVTRI 470 SSPQVEEGDS480 RFLANEVLQE490 NYTHLPKADI500 FALALTVVCA510 AGAEPLPRNG 520 DQWHEIRQGR530 LPRIPQVLSQ540 EFTELLKVMI550 HPDPERRPSA560 MALVKHSVLL 570
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GLU303
2.574
ILE305
2.403
GLY306
2.391
SER307
4.848
VAL313
2.782
LYS315
3.180
ALA326
3.032
ILE327
4.550
LYS328
2.634
GLU346
3.722
VAL360
2.627
ILE374
4.401
ASN376
2.576
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| Ligand Name: MK-1775 | Ligand Info | |||||
| Structure Description | CRYSTAL STRUCTURE OF HUMAN WEE1 KINASE DOMAIN IN COMPLEX WITH MK1775 | PDB:5V5Y | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [8] |
| PDB Sequence |
SRYTTEFHEL
302 EKIGSGEFGS312 VFKCVKRLDG322 CIYAIKRSKK332 PLAGSVDEQN342 ALREVYAHAV 352 LGQHSHVVRY362 FSAWAEDDHM372 LIQNEYCNGG382 SLADAISENY392 RIMSYFKEAE 402 LKDLLLQVGR412 GLRYIHSMSL422 VHMDIKPSNI432 FISRTKVMFK460 IGDLGHVTRI 470 SSPQVEEGDS480 RFLANEVLQE490 NYTHLPKADI500 FALALTVVCA510 AGAEPLPRNG 520 DQWHEIRQGR530 LPRIPQVLSQ540 EFTELLKVMI550 HPDPERRPSA560 MALVKHSVL |
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GLU303
3.328
LYS304
4.394
ILE305
2.545
GLY306
2.182
SER307
4.067
PHE310
2.827
VAL313
2.373
ALA326
3.223
ILE327
3.559
LYS328
2.320
GLU346
4.293
VAL360
2.460
ILE374
3.160
GLN375
4.766
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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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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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| Cell cycle | hsa04110 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Degree | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 9.66E-07 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 6.67E-01 |
| Neighborhood connectivity | 6.03E+01 | Topological coefficient | 2.85E-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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| 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 Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Cell cycle | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TGF_beta_Receptor Signaling Pathway | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | PLK1 signaling events | |||||
| Reactome | [+] 7 Reactome Pathways | + | ||||
| 1 | Polo-like kinase mediated events | |||||
| 2 | Cyclin E associated events during G1/S transition | |||||
| 3 | Cyclin A/B1 associated events during G2/M transition | |||||
| 4 | G2/M DNA replication checkpoint | |||||
| 5 | Cyclin A:Cdk2-associated events at S phase entry | |||||
| 6 | Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex | |||||
| 7 | Factors involved in megakaryocyte development and platelet production | |||||
| WikiPathways | [+] 9 WikiPathways | + | ||||
| 1 | G1 to S cell cycle control | |||||
| 2 | S Phase | |||||
| 3 | Retinoblastoma (RB) in Cancer | |||||
| 4 | Integrated Breast Cancer Pathway | |||||
| 5 | Mitotic G2-G2/M phases | |||||
| 6 | Mitotic G1-G1/S phases | |||||
| 7 | Factors involved in megakaryocyte development and platelet production | |||||
| 8 | Cell Cycle | |||||
| 9 | Cell Cycle Checkpoints | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7702). | |||||
| REF 3 | Targeting radiation-induced G(2) checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Mol Cancer Ther. 2011 Dec;10(12):2405-14. | |||||
| REF 4 | ClinicalTrials.gov (NCT04814108) A Study of ZN-c3 in Women With Recurrent or Persistent Uterine Serous Carcinoma. U.S. National Institutes of Health. | |||||
| REF 5 | Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor. Mol Cancer. 2009 Jun 8;8:34. | |||||
| REF 6 | Clinical pipeline report, company report or official report of Zentalis Pharmaceuticals. | |||||
| REF 7 | Receptor-based 3D-QSAR studies of checkpoint Wee1 kinase inhibitors. Eur J Med Chem. 2009 Apr;44(4):1383-95. | |||||
| REF 8 | Structural Basis of Wee Kinases Functionality and Inactivation by Diverse Small Molecule Inhibitors. J Med Chem. 2017 Sep 28;60(18):7863-7875. | |||||
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