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TTK protein kinase

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Target id: 2264

Nomenclature: TTK protein kinase

Abbreviated Name: TTK

Family: TTK family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 857 6q14.1 TTK TTK protein kinase
Mouse - 856 9 E2 Ttk Ttk protein kinase
Rat - 835 8 q31 Ttk Ttk protein kinase
Previous and Unofficial Names Click here for help
cancer/testis antigen 96 | CT96 | dual specificity protein kinase TTK | Esk1 | Mps1 | monopolar spindle kinase 1
Database Links Click here for help
Alphafold P33981 (Hs), P35761 (Mm)
BRENDA 2.7.12.1
CATH/Gene3D 1.25.40.10
ChEMBL Target CHEMBL3983 (Hs)
Ensembl Gene ENSG00000112742 (Hs), ENSMUSG00000038379 (Mm), ENSRNOG00000029055 (Rn)
Entrez Gene 7272 (Hs), 22137 (Mm), 315852 (Rn)
Human Protein Atlas ENSG00000112742 (Hs)
KEGG Enzyme 2.7.12.1
KEGG Gene hsa:7272 (Hs), mmu:22137 (Mm), rno:315852 (Rn)
OMIM 604092 (Hs)
Pharos P33981 (Hs)
RefSeq Nucleotide NM_001166691 (Hs), NM_009445 (Mm), NM_001108172 (Rn)
RefSeq Protein NP_003309 (Hs), NP_033471 (Mm), NP_001101642 (Rn)
SynPHARM 84036 (in complex with AZ3146)
84085 (in complex with BAY1161909)
84035 (in complex with MPI-0479605)
83753 (in complex with MPS1-IN-1)
84037 (in complex with NMS-P715)
UniProtKB P33981 (Hs), P35761 (Mm)
Wikipedia TTK (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human dual specificity protein kinase (TTK).
PDB Id:  3CEK
Resolution:  2.3Å
Species:  Human
References:  11
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human Mps1 (TTK) catalytic domain in complex with ATP.
PDB Id:  3HMN
Ligand:  ATP
Resolution:  2.7Å
Species:  Human
References:  4
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human TTK in complex with an inhibitor.
PDB Id:  6N6O
Ligand:  compound 20 [PMID: 30998356]
Resolution:  2.6Å
Species:  Human
References:  13
Image of receptor 3D structure from RCSB PDB
Description:  Introduction of a methyl group curbs metabolism of pyrido[3,4-d]pyrimidine MPS1 inhibitors and enables the discovery of the Phase 1 clinical candidate BOS172722.
PDB Id:  6H3K
Ligand:  BOS172722
Resolution:  2.48Å
Species:  Human
References:  17
Enzyme Reaction Click here for help
EC Number: 2.7.12.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
Ro3280 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pKd 3
⤷ pKd 7.3 (Kd 5.1x10-8 M) [3]
Description: Ambit selectivity screen at 1μM Ro3280.
BOS172722 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 10.0 pKi 17
⤷ pKi 10.0 (Ki 1.1x10-10 M) [17]
GNE-7915 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pKi 6
⤷ pKi 7.3 (Ki 5.3x10-8 M) [6]
compound 20 [PMID: 30998356] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.1 pIC50 13
⤷ pIC50 9.1 (IC50 7x10-10 M) [13]
Description: In vitro inhibitory activity using the proprietary LanthaScreen Eu kinase binding assay.
luvixasertib Small molecule or natural product Hs Inhibition 8.8 pIC50 12
⤷ pIC50 8.8 (IC50 1.7x10-9 M) [12]
MPI-0479605 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.7 pIC50 14
⤷ pIC50 8.7 (IC50 1.8x10-9 M) [14]
compound 27f [PMID: 25625617] Small molecule or natural product Primary target of this compound Hs Inhibition 8.6 pIC50 10
⤷ pIC50 8.6 (IC50 2.8x10-9 M) [10]
Description: Biochemical assay
compound 34h [PMID: 27055065] Small molecule or natural product Hs Inhibition 8.0 – 8.3 pIC50 8-9
⤷ pIC50 8.0 – 8.3 (IC50 1.1x10-8 – 5x10-9 M) [8-9]
empesertib Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition >8.0 pIC50 15
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [15]
BAY1217389 Small molecule or natural product Ligand has a PDB structure Hs Inhibition >8.0 pIC50 15
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [15]
BOS172722 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 17
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [17]
AZ3146 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition ~7.5 pIC50 7
⤷ pIC50 ~7.5 (IC50 ~3.5x10-8 M) [7]
Description: In vitro assay using a His-tagged catalytic domain fragment of MPS1 (amino acids 510–857).
NMS-P715 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 6.7 pIC50 2
⤷ pIC50 6.7 (IC50 1.82x10-7 M) [2]
MPS1-IN-1 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 6.4 pIC50 11
⤷ pIC50 6.4 (IC50 3.67x10-7 M) [11]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 5,16
Key to terms and symbols Click column headers to sort
Target used in screen: TTK
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.2 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 7.5 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.2 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 7.1 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 7.0 pKd
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 6.8 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: ...1
Key to terms and symbols Click column headers to sort
Target used in screen: nd/TTK
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Small molecule or natural product Hs Inhibitor Inhibition 18.9
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 31.1
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 36.3
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 46.1
Cdk2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 47.8
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 54.4
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 55.0
SU11652 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 59.8
SU9516 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 59.9
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 60.6
Displaying the top 10 most potent ligands  View all ligands in screen »

References

Show »

1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Caldarelli M, Angiolini M, Disingrini T, Donati D, Guanci M, Nuvoloni S, Posteri H, Quartieri F, Silvagni M, Colombo R. (2011) Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors. Bioorg Med Chem Lett, 21 (15): 4507-11. [PMID:21723120]

3. Chen S, Bartkovitz D, Cai J, Chen Y, Chen Z, Chu XJ, Le K, Le NT, Luk KC, Mischke S et al.. (2012) Identification of novel, potent and selective inhibitors of Polo-like kinase 1. Bioorg Med Chem Lett, 22 (2): 1247-50. [PMID:22172702]

4. Chu ML, Lang Z, Chavas LM, Neres J, Fedorova OS, Tabernero L, Cherry M, Williams DH, Douglas KT, Eyers PA. (2010) Biophysical and X-ray crystallographic analysis of Mps1 kinase inhibitor complexes. Biochemistry, 49 (8): 1689-701. [PMID:20099905]

5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

6. Estrada AA, Chan BK, Baker-Glenn C, Beresford A, Burdick DJ, Chambers M, Chen H, Dominguez SL, Dotson J, Drummond J et al.. (2014) Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem, 57 (3): 921-36. [PMID:24354345]

7. Hewitt L, Tighe A, Santaguida S, White AM, Jones CD, Musacchio A, Green S, Taylor SS. (2010) Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. J Cell Biol, 190 (1): 25-34. [PMID:20624899]

8. Hoelder S, Blagg J, Solanki S, Woodward H, Naud S, Bavetsias V, Sheldrake P, Innocenti P, Cheung J, Atrash B. (2014) Inhibitor compounds. Patent number: WO2014037750. Assignee: Cancer Research Technology Limited. Priority date: 07/09/2012. Publication date: 13/03/2014.

9. Innocenti P, Woodward HL, Solanki S, Naud S, Westwood IM, Cronin N, Hayes A, Roberts J, Henley AT, Baker R et al.. (2016) Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. J Med Chem, 59 (8): 3671-88. [PMID:27055065]

10. Kusakabe K, Ide N, Daigo Y, Itoh T, Yamamoto T, Hashizume H, Nozu K, Yoshida H, Tadano G, Tagashira S et al.. (2015) Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity. J Med Chem, 58 (4): 1760-75. [PMID:25625617]

11. Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararajan M, Manak MS, Kwon M, Choi HG, Sim T, Deveraux QL, Rottmann S et al.. (2010) Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nat Chem Biol, 6 (5): 359-68. [PMID:20383151]

12. Liu Y, Laufer R, Patel NK, Ng G, Sampson PB, Li SW, Lang Y, Feher M, Brokx R, Beletskaya I et al.. (2016) Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent. ACS Med Chem Lett, 7 (7): 671-5. [PMID:27437075]

13. Riggs JR, Elsner J, Cashion D, Robinson D, Tehrani L, Nagy M, Fultz KE, Krishna Narla R, Peng X, Tran T et al.. (2019) Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy. J Med Chem, 62 (9): 4401-4410. [PMID:30998356]

14. Tardif KD, Rogers A, Cassiano J, Roth BL, Cimbora DM, McKinnon R, Peterson A, Douce TB, Robinson R, Dorweiler I et al.. (2011) Characterization of the cellular and antitumor effects of MPI-0479605, a small-molecule inhibitor of the mitotic kinase Mps1. Mol Cancer Ther, 10 (12): 2267-75. [PMID:21980130]

15. Wengner AM, Siemeister G, Koppitz M, Schulze V, Kosemund D, Klar U, Stoeckigt D, Neuhaus R, Lienau P, Bader B et al.. (2016) Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity. Mol Cancer Ther, 15 (4): 583-92. [PMID:26832791]

16. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

17. Woodward HL, Innocenti P, Cheung KJ, Hayes A, Roberts J, Henley AT, Faisal A, Mak GW, Box G, Westwood IM et al.. (2018) Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722). J Med Chem, 61 (18): 8226-8240. [PMID:30199249]

How to cite this page

TTK family: TTK protein kinase. Last modified on 06/06/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2264.