Target Information
| Target General Information | Top | |||||
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| Target ID |
T96892
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| Target Name |
Maternal embryonic leucine zipper kinase (MELK)
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| Synonyms |
Protein kinase PK38; Protein kinase Eg3
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| Gene Name |
MELK
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 6 Target-related Diseases | + | ||||
| 1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
| 2 | Breast cancer [ICD-11: 2C60-2C6Y] | |||||
| 3 | Mature B-cell leukaemia [ICD-11: 2A82] | |||||
| 4 | Mature B-cell lymphoma [ICD-11: 2A85] | |||||
| 5 | Myelodysplastic syndrome [ICD-11: 2A37] | |||||
| 6 | Myeloproliferative neoplasm [ICD-11: 2A20] | |||||
| Function |
Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.
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| BioChemical Class |
Protein kinase superfamily. CAMK Ser/Thr protein kinase family
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MKDYDELLKYYELHETIGTGGFAKVKLACHILTGEMVAIKIMDKNTLGSDLPRIKTEIEA
LKNLRHQHICQLYHVLETANKIFMVLEYCPGGELFDYIISQDRLSEEETRVVFRQIVSAV AYVHSQGYAHRDLKPENLLFDEYHKLKLIDFGLCAKPKGNKDYHLQTCCGSLAYAAPELI QGKSYLGSEADVWSMGILLYVLMCGFLPFDDDNVMALYKKIMRGKYDVPKWLSPSSILLL QQMLQVDPKKRISMKNLLNHPWIMQDYNYPVEWQSKNPFIHLDDDCVTELSVHHRNNRQT MEDLISLWQYDHLTATYLLLLAKKARGKPVRLRLSSFSCGQASATPFTDIKSNNWSLEDV TASDKNYVAGLIDYDWCEDDLSTGAATPRTSQFTKYWTESNGVESKSLTPALCRTPANKL KNKENVYTPKSAVKNEEYFMFPEPKTPVNKNQHKREILTTPNRYTTPSKARNQCLKETPI KIPVNSTGTDKLMTGVISPERRCRSVELDLNQAHMEETPKRKGAKVFGSLERGLDKVITV LTRSKRKGSARDGPRRLKLHYNVTTTRLVNPDQLLNEIMSILPKKHVDFVQKGYTLKCQT QSDFGKVTMQFELEVCQLQKPDVVGIRRQRLKGDAWVYKRLVEDILSSCKV 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 | OTSSP167 | Drug Info | Phase 1 | Acute lymphoblastic leukaemia | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | OTSSP167 | Drug Info | [1], [2] | |||
| 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: Intedanib | Ligand Info | |||||
| Structure Description | Crystal structure of MELK in complex with an inhibitor | PDB:5MAF | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [3] |
| PDB Sequence |
PKDYDELLKY
10 YELHETIGTG20 GFAKVKLACH30 ILTGEMVAIK40 IMDKNTLDLP52 RIKTEIEALK 62 NLRHQHICQL72 YHVLETANKI82 FMVLEYCPGG92 ELFDYIISQD102 RLSEEETRVV 112 FRQIVSAVAY122 VHSQGYAHRD132 LKPENLLFDE142 YHKLKLIDFG152 LCAKSLAYAA 176 PELIQGKLGS188 EADVWSMGIL198 LYVLMCGFLP208 FDDDNVMALY218 KKIMRGKYDV 228 PKWLSPSSIL238 LLQQMLQVDP248 KKRISMKNLL258 NHPWIMQDYN268 YPVEWQSKNP 278 FIHLDDDCVT288 ELSVHHRNNR298 QTMEDLISLW308 QYDHLTATYL318 LLLAKKARGK 328 PVRLR
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GLU15
3.473
ILE17
3.206
GLY18
3.506
THR19
4.368
VAL25
3.682
LEU27
4.238
ALA38
3.409
LYS40
2.645
GLU57
3.561
LEU61
3.913
CYS70
3.772
LEU86
3.468
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| Ligand Name: VS-6063 | Ligand Info | |||||
| Structure Description | Crystal structure of MELK in complex with an inhibitor | PDB:5MAH | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [3] |
| PDB Sequence |
KDYDELLKYY
11 ELHETIGTGG21 FAKVKLACHI31 LTGEMVAIKI41 MDKNTLGSDL51 PRIKTEIEAL 61 KNLRHQHICQ71 LYHVLETANK81 IFMVLEYCPG91 GELFDYIISQ101 DRLSEEETRV 111 VFRQIVSAVA121 YVHSQGYAHR131 DLKPENLLFD141 EYHKLKLIDF151 GLCAKSLAYA 175 APELIQGKLG187 SEADVWSMGI197 LLYVLMCGFL207 PFDDDNVMAL217 YKKIMRGKYD 227 VPKWLSPSSI237 LLLQQMLQVD247 PKKRISMKNL257 LNHPWIMQDY267 NYPVEWQSKN 277 PFIHLDDDCV287 TELSVHHRNN297 RQTMEDLISL307 WQYDHLTATY317 LLLLAKKARG 327 KPVRLR
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ILE17
3.604
GLY18
4.119
THR19
3.660
GLY20
3.541
ALA23
3.692
VAL25
3.322
ALA38
3.509
LYS40
3.361
CYS70
3.325
LEU86
3.279
GLU87
3.220
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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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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 | 19 | Degree centrality | 2.04E-03 | Betweenness centrality | 3.68E-05 |
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| Closeness centrality | 2.20E-01 | Radiality | 1.39E+01 | Clustering coefficient | 7.43E-01 |
| Neighborhood connectivity | 5.23E+01 | Topological coefficient | 1.94E-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 | ||||||
| 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 | Maternal embryonic leucine zipper kinase is a novel target for proliferation-associated high-risk myeloma.Haematologica. 2018 Feb;103(2):325-335. | |||||
| REF 3 | The target landscape of clinical kinase drugs. Science. 2017 Dec 1;358(6367):eaan4368. | |||||
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