Target Information
| Target General Information | Top | |||||
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| Target ID |
T74977
(Former ID: TTDR01110)
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| Target Name |
Dual specificity protein kinase TTK (MPS1)
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| Synonyms |
Tyrosine threonine kinase; Phosphotyrosine picked threonine-protein kinase; PYT; MPS1L1
Click to Show/Hide
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| Gene Name |
TTK
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint. Phosphorylates proteins on serine, threonine, and tyrosine.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.12.1
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| Sequence |
MESEDLSGRELTIDSIMNKVRDIKNKFKNEDLTDELSLNKISADTTDNSGTVNQIMMMAN
NPEDWLSLLLKLEKNSVPLSDALLNKLIGRYSQAIEALPPDKYGQNESFARIQVRFAELK AIQEPDDARDYFQMARANCKKFAFVHISFAQFELSQGNVKKSKQLLQKAVERGAVPLEML EIALRNLNLQKKQLLSEEEKKNLSASTVLTAQESFSGSLGHLQNRNNSCDSRGQTTKARF LYGENMPPQDAEIGYRNSLRQTNKTKQSCPFGRVPVNLLNSPDCDVKTDDSVVPCFMKRQ TSRSECRDLVVPGSKPSGNDSCELRNLKSVQNSHFKEPLVSDEKSSELIITDSITLKNKT ESSLLAKLEETKEYQEPEVPESNQKQWQSKRKSECINQNPAASSNHWQIPELARKVNTEQ KHTTFEQPVFSVSKQSPPISTSKWFDPKSICKTPSSNTLDDYMSCFRTPVVKNDFPPACQ LSTPYGQPACFQQQQHQILATPLQNLQVLASSSANECISVKGRIYSILKQIGSGGSSKVF QVLNEKKQIYAIKYVNLEEADNQTLDSYRNEIAYLNKLQQHSDKIIRLYDYEITDQYIYM VMECGNIDLNSWLKKKKSIDPWERKSYWKNMLEAVHTIHQHGIVHSDLKPANFLIVDGML KLIDFGIANQMQPDTTSVVKDSQVGTVNYMPPEAIKDMSSSRENGKSKSKISPKSDVWSL GCILYYMTYGKTPFQQIINQISKLHAIIDPNHEIEFPDIPEKDLQDVLKCCLKRDPKQRI SIPELLAHPYVQIQTHPVNQMAKGTTEEMKYVLGQLVGLNSPNSILKAAKTLYEHYSGGE SHNSSSSKTFEKKRGKK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T50S1H | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | BAY1161909 | Drug Info | Phase 1 | Solid tumour/cancer | [2] | |
| 2 | BOS172722 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
| 3 | CFI-402257 | Drug Info | Phase 1 | Solid tumour/cancer | [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 8 Inhibitor drugs | + | ||||
| 1 | BAY1161909 | Drug Info | [1] | |||
| 2 | BOS172722 | Drug Info | [3] | |||
| 3 | CFI-402257 | Drug Info | [5] | |||
| 4 | Tricyclic isoxazoloquinazoline derivative 2 | Drug Info | [6] | |||
| 5 | Tricyclic isoxazoloquinazoline derivative 3 | Drug Info | [6] | |||
| 6 | Tricyclic isoxazoloquinazoline derivative 4 | Drug Info | [6] | |||
| 7 | 2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One | Drug Info | [7] | |||
| 8 | GNE-7915 | Drug Info | [8] | |||
| 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: Adenosine triphosphate | Ligand Info | |||||
| Structure Description | Crystal structure of human Mps1 catalytic domain in complex with ATP | PDB:3HMN | ||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [9] |
| PDB Sequence |
ECISVKGRIY
525 SILKQIGSGG535 SSKVFQVLNE545 KKQIYAIKYV555 NLEEADNQTL565 DSYRNEIAYL 575 NKLQQHSDKI585 IRLYDYEITD595 QYIYMVMECG605 NIDLNSWLKK615 KKSIDPWERK 625 SYWKNMLEAV635 HTIHQHGIVH645 SDLKPANFLI655 VDGMLKLIDF665 GIANQMVGTV 687 NYMPPEAIKD697 MISPKSDVWS719 LGCILYYMTY729 GKTPFQQIIN739 QISKLHAIID 749 PNHEIEFPDI759 PEKDLQDVLK769 CCLKRDPKQR779 ISIPELLAHP789 YVQIQ |
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| Ligand Name: BAY1161909 | Ligand Info | |||||
| Structure Description | TTK kinase domain in complex with BAY 1161909 | PDB:5N9S | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [10] |
| PDB Sequence |
QSMSVKGRIY
525 SILKQIGSGG535 SSKVFQVLNE545 KKQIYAIKYV555 NLEEADNQTL565 DSYRNEIAYL 575 NKLQQHSDKI585 IRLYDYEITD595 QYIYMVMECG605 NIDLNSWLKK615 KKSIDPWERK 625 SYWKNMLEAV635 HTIHQHGIVH645 SDLKPANFLI655 VDGMLKLIDF665 GIANQMQPDS 682 QVGVNYMPPE693 AIKDKISPKS715 DVWSLGCILY725 YMTYGKTPFQ735 QIINQISKLH 745 AIIDPNHEIE755 FPDIPEKDLQ765 DVLKCCLKRD775 PKQRISIPEL785 LAHPYVQIQ |
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LYS529
4.067
ILE531
3.673
VAL539
4.194
GLN541
3.490
ALA551
3.501
LYS553
3.088
VAL555
3.818
TYR568
3.404
GLU571
3.624
ILE572
3.761
ILE586
4.107
ILE598
3.600
MET600
3.031
MET602
3.124
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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 | 33 | Degree centrality | 3.55E-03 | Betweenness centrality | 2.60E-05 |
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| Closeness centrality | 2.11E-01 | Radiality | 1.37E+01 | Clustering coefficient | 6.80E-01 |
| Neighborhood connectivity | 4.42E+01 | Topological coefficient | 1.71E-01 | Eccentricity | 13 |
| 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 | |||||
|---|---|---|---|---|---|---|
| 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 | [+] 1 KEGG Pathways | + | ||||
| 1 | Cell cycle | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | IL2 Signaling Pathway | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Retinoblastoma (RB) in Cancer | |||||
| References | Top | |||||
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| REF 1 | National Cancer Institute Drug Dictionary (drug id 761238). | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040625) | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | ClinicalTrials.gov (NCT02792465) A Study of Investigational Drug CFI-402257 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 5 | Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3127-3132. | |||||
| REF 6 | Protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK) inhibitors: a patent review (2010-2015).Expert Opin Ther Pat. 2017 Jan;27(1):37-48. | |||||
| REF 7 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 8 | Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2014 Feb 13;57(3):921-36. | |||||
| REF 9 | Biophysical and X-ray crystallographic analysis of Mps1 kinase inhibitor complexes. Biochemistry. 2010 Mar 2;49(8):1689-701. | |||||
| REF 10 | Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity. J Mol Biol. 2017 Jul 7;429(14):2211-2230. | |||||
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