TTK

Summary

TTK (TTK protein kinase, HGNC:12401) is a protein-coding gene on chromosome 6q14.1, encoding Dual specificity protein kinase TTK (P33981). Involved in mitotic spindle assembly checkpoint signaling, a process that delays anaphase until chromosomes are bioriented on the spindle, and in the repair of incorrect mitotic kinetochore-spindle microtubule attachments. It is a selective cancer dependency (DepMap: 89.9% of cell lines).

This gene encodes a dual specificity protein kinase with the ability to phosphorylate tyrosine, serine and threonine. Associated with cell proliferation, this protein is essential for chromosome alignment at the centromere during mitosis and is required for centrosome duplication. It has been found to be a critical mitotic checkpoint protein for accurate segregation of chromosomes during mitosis. Tumorigenesis may occur when this protein fails to degrade and produces excess centrosomes resulting in aberrant mitotic spindles. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7272 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 136 total — 1 pathogenic
• GTEx eGene: eQTL in 8 tissues, sQTL in 2 (q < 0.05)
• Drug target: yes — 2 curated mechanism-of-action drugs; 36 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Cancer dependency (DepMap): dependent in 89.9% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.67 (unconstrained)
• MANE Select transcript: NM_003318
• Interaction hub: 1,828 STRING partners (top 9% of genes corpus-wide)
• Notable: 136 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12401
Approved symbol	TTK
Name	TTK protein kinase
Location	6q14.1
Locus type	gene with protein product
Status	Approved
Aliases	PYT, MPS1, MPS1L1, CT96, MPH1
Ensembl gene	ENSG00000112742
Ensembl biotype	protein_coding
OMIM	604092
Entrez	7272

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000369798

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 1, TSL 4: 5, TSL 5: 2

ENST00000369798, ENST00000230510, ENST00000430061, ENST00000502580, ENST00000504040, ENST00000504590, ENST00000509313, ENST00000509894, ENST00000511260, ENST00000515751, ENST00000627129, ENST00000867612, ENST00000936244, ENST00000936245, ENST00000936246, ENST00000936247, ENST00000936248, ENST00000936249, ENST00001064207, ENST00001140456

RefSeq mRNA: 4 — MANE Select: NM_003318 NM_001166691, NM_001437890, NM_001438341, NM_003318

CCDS: CCDS4993, CCDS55040

Canonical transcript exons

ENST00000369798 — 22 exons

Exon	Start	End
ENSE00000759354	80011729	80011801
ENSE00000759356	80011886	80011980
ENSE00000759358	80013279	80013366
ENSE00000759363	80027885	80028011
ENSE00000759364	80031467	80031559
ENSE00000759365	80034985	80035142
ENSE00000759366	80035266	80035417
ENSE00000759368	80037967	80038047
ENSE00000759370	80040196	80040280
ENSE00000759371	80040606	80040703
ENSE00000798027	80005842	80005982
ENSE00000798028	80036475	80036599
ENSE00001450959	80004649	80004713
ENSE00002035648	80042119	80042527
ENSE00002036427	80011434	80011548
ENSE00003498599	80022324	80022472
ENSE00003530004	80008386	80008492
ENSE00003579064	80026378	80026514
ENSE00003579671	80014463	80014586
ENSE00003601890	80039696	80039872
ENSE00003604712	80010814	80010957
ENSE00003688914	80007809	80008031

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 97.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.4047 / max 422.9215, expressed in 1127 samples.

Highest expression (Bgee): secondary oocyte, ventricular zone, oocyte, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TTK is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 8 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

10 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells EBV-transformed lymphocytes	sqtl	2.9e-11	+0.77	6:80011016:G:A
Cells Cultured fibroblasts	sqtl	6.7e-10	+0.48	6:79992059:C:T
Testis	eqtl	1.9e-06	-0.16	6:80094556:T:C
Cells Cultured fibroblasts	eqtl	7.6e-05	-0.10	6:80040255:A:C
Adipose Subcutaneous	eqtl	2.3e-03	-0.16	6:80004496:G:C
Nerve Tibial	eqtl	4.2e-03	-0.99	6:80722593:C:A
Stomach	eqtl	1.0e-02	-0.37	6:80493350:C:T
Brain Substantia nigra	eqtl	2.8e-02	+1.56	6:80049994:G:A
Brain Cerebellar Hemisphere	eqtl	2.9e-02	+0.60	6:79344046:C:G
Lung	eqtl	5.0e-02	-0.32	6:79050077:G:GT

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
68701	8.2074	1116
68700	0.1973	77

Top tissues by expression

showing 100 of 282 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.85	gold quality
ventricular zone	UBERON:0003053	95.55	gold quality
oocyte	CL:0000023	93.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.45	gold quality
ganglionic eminence	UBERON:0004023	90.27	gold quality
sperm	CL:0000019	89.89	gold quality
embryo	UBERON:0000922	89.16	gold quality
male germ cell	CL:0000015	87.95	gold quality
trabecular bone tissue	UBERON:0002483	86.65	gold quality
testis	UBERON:0000473	85.19	gold quality
right testis	UBERON:0004534	85.04	gold quality
left testis	UBERON:0004533	84.87	gold quality
bone marrow	UBERON:0002371	83.59	gold quality
thymus	UBERON:0002370	80.52	gold quality
rectum	UBERON:0001052	77.91	gold quality
stromal cell of endometrium	CL:0002255	77.88	gold quality
bone marrow cell	CL:0002092	76.38	gold quality
adrenal tissue	UBERON:0018303	76.02	gold quality
esophagus mucosa	UBERON:0002469	75.22	gold quality
lower esophagus mucosa	UBERON:0035834	75.05	gold quality
vermiform appendix	UBERON:0001154	74.19	gold quality
mucosa of transverse colon	UBERON:0004991	73.65	gold quality
esophagus squamous epithelium	UBERON:0006920	73.37	silver quality
endometrium epithelium	UBERON:0004811	72.93	gold quality
oral cavity	UBERON:0000167	72.91	gold quality
adult organism	UBERON:0007023	72.32	gold quality
gingival epithelium	UBERON:0001949	72.26	silver quality
caecum	UBERON:0001153	70.56	gold quality
colonic epithelium	UBERON:0000397	70.50	gold quality
lymph node	UBERON:0000029	70.36	gold quality
epithelium of esophagus	UBERON:0001976	69.86	silver quality
squamous epithelium	UBERON:0006914	69.53	silver quality
gingiva	UBERON:0001828	69.50	silver quality
tonsil	UBERON:0002372	68.12	gold quality
cortical plate	UBERON:0005343	67.91	gold quality
placenta	UBERON:0001987	67.52	gold quality
duodenum	UBERON:0002114	67.26	gold quality
endometrium	UBERON:0001295	66.87	gold quality
amniotic fluid	UBERON:0000173	66.39	gold quality
upper leg skin	UBERON:0004262	66.25	gold quality
colonic mucosa	UBERON:0000317	65.99	gold quality
smooth muscle tissue	UBERON:0001135	65.29	gold quality
mucosa of sigmoid colon	UBERON:0004993	65.13	gold quality
jejunal mucosa	UBERON:0000399	65.12	gold quality
skin of abdomen	UBERON:0001416	64.56	gold quality
tongue squamous epithelium	UBERON:0006919	64.45	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	64.35	gold quality
hair follicle	UBERON:0002073	63.88	gold quality
skin of leg	UBERON:0001511	63.46	gold quality
buccal mucosa cell	CL:0002336	63.43	silver quality
transverse colon	UBERON:0001157	62.73	gold quality
zone of skin	UBERON:0000014	62.61	gold quality
islet of Langerhans	UBERON:0000006	61.53	gold quality
cartilage tissue	UBERON:0002418	61.31	gold quality
spleen	UBERON:0002106	61.00	gold quality
right adrenal gland	UBERON:0001233	60.73	gold quality
tibia	UBERON:0000979	60.71	silver quality
esophagus	UBERON:0001043	60.69	gold quality
small intestine	UBERON:0002108	60.33	gold quality
small intestine Peyer’s patch	UBERON:0003454	59.95	gold quality
stomach	UBERON:0000945	59.73	gold quality
pancreatic ductal cell	CL:0002079	59.67	silver quality
left adrenal gland cortex	UBERON:0035825	59.44	gold quality
vagina	UBERON:0000996	59.43	gold quality
adrenal gland	UBERON:0002369	59.27	gold quality
body of stomach	UBERON:0001161	59.24	gold quality
intestine	UBERON:0000160	59.19	gold quality
left adrenal gland	UBERON:0001234	59.16	gold quality
right adrenal gland cortex	UBERON:0035827	58.75	gold quality
large intestine	UBERON:0000059	58.10	gold quality
gall bladder	UBERON:0002110	57.99	gold quality
adrenal cortex	UBERON:0001235	57.96	gold quality
colon	UBERON:0001155	57.59	gold quality
epithelium of nasopharynx	UBERON:0001951	56.76	silver quality
decidua	UBERON:0002450	56.55	gold quality
jejunum	UBERON:0002115	56.30	gold quality
uterus	UBERON:0000995	56.24	gold quality
ileal mucosa	UBERON:0000331	55.57	gold quality
female reproductive system	UBERON:0000474	55.40	gold quality
descending thoracic aorta	UBERON:0002345	55.05	gold quality
mouth mucosa	UBERON:0003729	54.87	gold quality
leukocyte	CL:0000738	54.28	gold quality
mononuclear cell	CL:0000842	54.05	gold quality
monocyte	CL:0000576	53.94	gold quality
minor salivary gland	UBERON:0001830	53.80	gold quality
nasal cavity mucosa	UBERON:0001826	53.58	gold quality
pigmented layer of retina	UBERON:0001782	53.48	gold quality
pancreas	UBERON:0001264	53.45	gold quality
blood	UBERON:0000178	53.44	gold quality
metanephros	UBERON:0000081	52.95	gold quality
lung	UBERON:0002048	52.94	gold quality
cortex of kidney	UBERON:0001225	52.75	gold quality
cervix squamous epithelium	UBERON:0006922	52.55	gold quality
skin of hip	UBERON:0001554	52.52	gold quality
saliva-secreting gland	UBERON:0001044	52.03	gold quality
upper lobe of lung	UBERON:0008948	52.03	gold quality
anatomical system	UBERON:0000467	51.75	gold quality
cerebellar vermis	UBERON:0004720	51.73	gold quality
material anatomical entity	UBERON:0000465	51.70	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.08

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thymus	tissue	43.4
Testis	tissue	32.1	high
Bone marrow	tissue	23.9	medium
Tonsil	tissue	8.4	high
Lymph node	tissue	7.6	high
Rectum	tissue	5.5	high
Colon	tissue	4.5	medium
Appendix	tissue	4.0	medium
Esophagus	tissue	3.9	medium
Small intestine	tissue	3.9	medium
Placenta	tissue	3.7	medium
Duodenum	tissue	3.7	medium
Skin 1	tissue	3.4	medium
Stomach 1	tissue	3.1	medium
Breast	tissue	2.1	medium
Retina	tissue	1.7
Smooth muscle	tissue	1.6	not detected
Cerebellum	tissue	1.5	not detected
Ovary	tissue	1.4	low
Vagina	tissue	1.4	medium
Basal ganglia	tissue	1.2	low
Spleen	tissue	1.2	low
Urinary bladder	tissue	1.1	medium
Putamen	tissue	1.1
Prefrontal cortex	tissue	0.9
Cerebral cortex	tissue	0.9	low
Endometrium 1	tissue	0.9	low
Hippocampal formation	tissue	0.9
Entorhinal cortex	tissue	0.9
Ventral forebrain	tissue	0.9
Retrosplenial and cingulate cortex	tissue	0.9
Olfactory bulb	tissue	0.9
Retrosplenial cortex	tissue	0.9
Pons	tissue	0.8
Amygdala	tissue	0.8
Lung	tissue	0.8	low
Spinal cord	tissue	0.8
Prostate	tissue	0.8	medium
Septum	tissue	0.8
Cervix	tissue	0.7	low
Motor cortex	tissue	0.7
Midbrain	tissue	0.7
Medulla oblongata	tissue	0.7
Superior colliculi	tissue	0.7
Adrenal gland	tissue	0.7	not detected
Periaqueductal gray	tissue	0.7
Temporal cortex	tissue	0.7
Occipital cortex	tissue	0.7
Insular cortex	tissue	0.7
Adipose tissue	tissue	0.6	not detected
Thalamus	tissue	0.6
Hypothalamus	tissue	0.6
Substantia nigra	tissue	0.6
Fallopian tube	tissue	0.6	medium
Somatosensory cortex	tissue	0.6
Liver	tissue	0.5	not detected
Gallbladder	tissue	0.5	low
Corpus callosum	tissue	0.5
Caudate putamen	tissue	0.5
Thyroid gland	tissue	0.4	low

Brain sub-regions (HPA Brain Atlas): detected in 187; highest nTPM — Dorsal hippocampus (0.8), Dorsal spinal cord (0.8), Subiculum (0.8), Ventral hippocampus (0.8), Ventral spinal cord (0.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDR2, E2F4, TP53

miRNA regulators (miRDB)

Targeting TTK by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

24 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-5697	99.39	67.74	1249
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-5590-5P	98.81	68.78	969
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-335-5P	97.10	68.12	1022
HSA-MIR-376A-2-5P	96.43	68.06	715
HSA-MIR-759	96.16	66.77	873

Functional genomics

gnomAD constraint: pLI 2.99e-07, LOEUF 0.666, missense Z 0.749 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000369798 — one region, missense o/e 0.93. DepMap (CRISPR cell-line fitness): dependent in 89.9% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): CAL-78 (-1.797), KP-N-YN (-1.619), SF126 (-1.57), OS-RC-2 (-1.512), RCM-1 (-1.503), AML-193 (-1.479), Set-2 (-1.442), 42-MG-BA (-1.431), SNU-1105 (-1.38), UM-UC-3 (-1.366), COLO 201 (-1.334), NCI-H2171 (-1.317), NCI-H1694 (-1.313), NCI-H2052 (-1.302), SLR 24 (-1.283).

Literature-anchored findings (GeneRIF, showing 40)

• human Mps1(TTK kinase) is essential for the establishment and/or maintenance of the spindle assembly checkpoint, but dispensable for centrosome duplication. (PMID:11927556)
• is required by cells to arrest in mitosis in response to spindle defects and kinetochore defects resulting from the loss of the kinesin-like protein (PMID:12686615)
• is required for centrosome duplication and for the normal progression of mitosis (PMID:14657364)
• The inter-relationship between TTK and TACC2 established provides new avenue to study centrosome and spindle dynamics underlying cell divisional control. (PMID:15304323)
• TTK functions upstream from CHK2 in response to DNA damage (PMID:15618221)
• findings indicate that Aurora-A and hMPS1 aberrations are uncommon in aggressive lymphomas but Aurora-A overexpression may contribute to numerical chromosomal alterations in occasional mantle cell lymphomas (PMID:16080195)
• MPS1 is negatively regulated by the p53 protein after DNA damage by SN-38. The lack of suppression of MPS1 in p53-deficient cells leads to damage-induced apoptosis. (PMID:16446370)
• Results suggest that MPS1-dependent BLM phosphorylation is important for ensuring accurate chromosome segregation, and its deregulation may contribute to cancer. (PMID:16864798)
• analysis of a novel functional link between Mps1 and Smads in a non-canonical Smad signaling pathway (PMID:17452325)
• Mortalin binds to Mps1, and is phosphorylated by Mps1 on Thr62 and Ser65 (PMID:17573779)
• site-specific Mps1 autophosphorylation within the activation loop is required for full activity in vitro and function in vivo. (PMID:17728254)
• Data show that TTK protein kinase, lymphocyte antigen 6 complex locus K and insulin-like growth factor (IGF)-II mRNA binding protein 3 are tumor-associated antigens recognized by cytotoxic T lymphocytes and HLA-A24-restricted epitope peptides. (PMID:17784873)
• Mps1 mediates cyclin A-dependent centrosome reduplication (PMID:17804818)
• PRP4 is a spindle assembly checkpoint protein required for MPS1 localization to the kinetochores. (PMID:17998396)
• B-Raf(V600E) signaling deregulates the mitotic spindle checkpoint through stabilizing Mps1 levels in melanoma cells. (PMID:18071315)
• the endogenous Mps1 in mitotic HeLa cells is phosphorylated on T676, a residue in the activation loop. (PMID:18083840)
• MPS1 phosphorylates borealin to control aurora kinase activity and chromosome alignment. (PMID:18243099)
• crystallographic analysis of the catalytic domain of the mitotic checkpoint kinase Mps1 in complex with SP600125 (PMID:18480048)
• In human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2. (PMID:18541701)
• Results reveal the complexity of Mps1 regulation by multi-site phosphorylation, and demonstrate conclusively that phosphorylated Mps1 associates with centrosomes in mitotic human cells. (PMID:18680479)
• TTK controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress. (PMID:18794806)
• Results demonstrate that phosphorylation of Mps1 at T12 and S15 is required for Mps1 recruitment to the kinetochore. (PMID:18923149)
• Mps1 is a major but not the exclusive kinase that specifies BubR1 phosphorylation in vivo. (PMID:19015317)
• identified Mps1 autophosphorylation sites in the activation and the P+1 loops. Whereas activation loop autophosphorylation enhances kinase activity, autophosphorylation at the P+1 loop (T686) is associated with the active kinase (PMID:19120698)
• a regulatory loop between TTK/hMps1 and CHK2 whereby DNA damage-activated CHK2 may facilitate the stabilization of TTK/hMps1, therefore maintaining the checkpoint control. (PMID:19151762)
• Stabilization and activation of p53 by spindle disruption requires the spindle checkpoint kinase TTK/hMps1. (PMID:19332559)
• Microtubule inhibitor-induced phosphorylation of BNIP3, Bcl-2 and Bcl-xL occurs independently of the AKT/mTor and JNK kinase pathways and requires Mps1 mitotic checkpoint kinase activity (PMID:20100468)
• Mps1 has multiple controls over mitotic checkpoint activity; short-term inhibition of Mps1 catalytic activity is sufficient to kill cells (PMID:20422024)
• Mps1 kinase activity ensures accurate chromosome segregation through its recruitment to kinetochores of mitotic checkpoint proteins (PMID:20624898)
• Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. (PMID:20624899)
• Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine. (PMID:20624901)
• Mps1 directs the assembly of Cdc20 inhibitory complexes during interphase and mitosis to control M phase timing and spindle checkpoint signaling. (PMID:20624902)
• the sequential actions of the APC-c(Cdc20) and APC-c(Cdh1) ubiquitin ligases regulate the clearance of Mps1 levels and are critical for Mps1 functions during the cell cycle in human cells. (PMID:20729194)
• Data show that OAZ promotes the removal of Mps1 from centrosomes, and centrosome overproduction caused by reducing OAZ activity requires Mps1. (PMID:20861309)
• Mps1 mutant without the unstructured tail region is defective in mediating spindle assembly checkpoint activation. (PMID:20884615)
• Release of Mps1 from kinetochores is essential for mitotic checkpoint silencing and a fast metaphase-to-anaphase transition. (PMID:20937696)
• Mps1-dependent phosphorylation of Cetn2 stimulates the canonical centriole assembly pathway. (PMID:20980622)
• High frequency of TTK mutations is associated with microsatellite-unstable colorectal cancer. (PMID:21163887)
• Data suggest that high levels of Mps1 in breast cancer cells likely contribute to these cells tolerating aneuploidy. (PMID:21402910)
• conditional inactivation of Mps1 inactivates the mitotic checkpoint, increases chromosome alignment defects, and compromises cell viability in vitro (PMID:21475725)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttk	ENSDARG00000041361
mus_musculus	Ttk	ENSMUSG00000038379
rattus_norvegicus	Ttk	ENSRNOG00000029055

Paralogs (2): TLK2 (ENSG00000146872), TLK1 (ENSG00000198586)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1194921) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal embryo implantation	1
reduced female fertility	1
decreased litter size	1
abnormal inner cell mass morphology	1
aneuploidy	1
abnormal female meiosis	1
abnormal meiotic spindle assembly checkpoint	1
embryonic lethality between implantation and somite formation, complete penetrance	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to organogenesis	1
enhanced polar body extrusion	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	Q4R945	96.6%	Diamond
Sus scrofa	F1SPM8	92.3%	Diamond
Bos taurus	F1MH24	91.8%	Diamond
Streptomyces coelicolor A3(2)	P54741	71.6%	Diamond
Streptomyces griseus	P54742	71.4%	Diamond
Candida albicans SC5314	Q5A961	55.6%	Diamond
Dictyostelium discoideum	Q54UL8	47.8%	Diamond
Schizosaccharomyces pombe 972h-	O94235	46.8%	Diamond
Arabidopsis thaliana	Q84VX4	46.7%	Diamond
Saccharomyces cerevisiae S288C	P54199	44.6%	Diamond
Encephalitozoon cuniculi GB-M1	Q8SSH4	44.2%	Diamond
Toxoplasma gondii	Q2PAY2	41.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ELOVL4	protein-coding	6785
BCKDHB	protein-coding	594

Protein

Protein identifiers

Dual specificity protein kinase TTK — P33981 (reviewed: P33981)

Alternative names: Phosphotyrosine picked threonine-protein kinase

All UniProt accessions (5): P33981, D6REX1, D6RF82, D6RFY1, D6RIC6

UniProt curated annotations — full annotation on UniProt →

Function. Involved in mitotic spindle assembly checkpoint signaling, a process that delays anaphase until chromosomes are bioriented on the spindle, and in the repair of incorrect mitotic kinetochore-spindle microtubule attachments. Phosphorylates MAD1L1 to promote the mitotic spindle assembly checkpoint. Phosphorylates CDCA8/Borealin leading to enhanced AURKB activity at the kinetochore. Phosphorylates SKA3 at ‘Ser-34’ leading to dissociation of the SKA complex from microtubules and destabilization of microtubule-kinetochore attachments. Phosphorylates KNL1, KNTC1 and autophosphorylates. Phosphorylates MCRS1 which enhances recruitment of KIF2A to the minus end of spindle microtubules and promotes chromosome alignment.

Subunit / interactions. Interacts with TPR; the interactions occurs in a microtubule-independent manner. Interacts with MAD1L1 and MAD2L1.

Tissue specificity. Present in rapidly proliferating cell lines.

Activity regulation. Inhibited by the ATP-competitive kinase inhibitor, SP600125.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P33981-1	1	yes
P33981-2	2

RefSeq proteins (4): NP_001160163, NP_001424819, NP_001425270, NP_003309* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR027084	Mps1_cat	Domain

Pfam: PF00069

Enzyme classification (BRENDA)

• EC 2.7.12.1 — dual-specificity kinase (BRENDA: 51 organisms, 125 substrates, 188 inhibitors, 14 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.019–0.1185	7
HISTONE H1	0.006–0.012	5

Catalyzed reactions (Rhea)

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (71 total): helix 25, modified residue 14, strand 12, turn 4, region of interest 2, sequence variant 2, mutagenesis site 2, sequence conflict 2, compositionally biased region 2, binding site 2, chain 1, domain 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

showing 30 of 78 structures by resolution:

PDB	Title	Method	Resolution (Å)
4H7Y	Crystal structure of the tetratricopeptide repeat (TPR) motif of human dual specificity …	X-RAY DIFFRACTION	1.8
4JS8	Crystal structure of TTK kinase domain with an inhibitor: 401348	X-RAY DIFFRACTION	1.94
7LQD	Structure of Human MPS1 (TTK) covalently bound to RMS-07 inhibitor	X-RAY DIFFRACTION	1.95
5EI6	Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 …	X-RAY DIFFRACTION	2.01
5AP1	Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug …	X-RAY DIFFRACTION	2.05
5AP6	Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug …	X-RAY DIFFRACTION	2.1
5N93	TTK kinase domain in complex with TC-Mps1-12	X-RAY DIFFRACTION	2.1
5AP0	Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug …	X-RAY DIFFRACTION	2.15
5EI8	Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 …	X-RAY DIFFRACTION	2.17
5EH0	Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 …	X-RAY DIFFRACTION	2.18
5EHO	Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 …	X-RAY DIFFRACTION	2.18
4B94	Crystal structure of human Mps1 TPR domain	X-RAY DIFFRACTION	2.2
4JT3	Crystal Structure of TTK kinase domain with an inhibitor: 400740	X-RAY DIFFRACTION	2.2
5MRB	Crystal structure of human Mps1 (TTK) in complex with Cpd-5	X-RAY DIFFRACTION	2.2
5EHY	Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 …	X-RAY DIFFRACTION	2.26
5N87	TTK kinase domain in complex with NTRC 0066-0	X-RAY DIFFRACTION	2.29
3CEK	Crystal structure of human dual specificity protein kinase (TTK)	X-RAY DIFFRACTION	2.3
3HMP	Crystal structure of human Mps1 catalytic domain in complex with a quinazolin ligand …	X-RAY DIFFRACTION	2.3
3WZK	CRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH …	X-RAY DIFFRACTION	2.3
5N84	TTK kinase domain in complex with Mps-BAY2b	X-RAY DIFFRACTION	2.3
5N9S	TTK kinase domain in complex with BAY 1161909	X-RAY DIFFRACTION	2.3
6TNC	X-RAY STRUCTURE OF MPS1 IN COMPLEX WITH COMPOUND 46	X-RAY DIFFRACTION	2.3
7CIL	Crystal structure of TTK kinase domain in complex with compound 7	X-RAY DIFFRACTION	2.3
4ZEG	Crystal structure of TTK kinase domain in complex with a pyrazolopyrimidine inhibitor	X-RAY DIFFRACTION	2.33
4C4F	Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic …	X-RAY DIFFRACTION	2.36
4O6L	Crystal Structure of TTK kinase domain with an inhibitor: 401498 …	X-RAY DIFFRACTION	2.38
3HMO	Crystal structure of human Mps1 catalytic domain in complex with the inhibitor …	X-RAY DIFFRACTION	2.4
3VQU	CRYSTAL STRUCTURE OF HUMAN MPS1 CATALYTIC DOMAIN IN COMPLEX WITH …	X-RAY DIFFRACTION	2.4
7CHN	Crystal structure of TTK kinase domain in complex with compound 9	X-RAY DIFFRACTION	2.4
7CHT	Crystal structure of TTK kinase domain in complex with compound 30	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P33981-F1	64.11	0.36

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Predicted intracellular proteins, Plasma proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoli

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
647	proton acceptor

Ligand- & substrate-binding residues (2)

Position	Role
531–539	ATP
553	ATP

Post-translational modifications (14)

Type	Positions
Phosphoserine	7, 37, 80, 281, 317, 321, 363, 393, 436, 455, 821
Phosphothreonine	33, 360
N-acetylmethionine	1

Mutagenesis-validated functional residues (2)

Position	Phenotype
664	loss of kinase activity.
686	loss of kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 403 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, MODULE_52, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, HORIUCHI_WTAP_TARGETS_DN, GNF2_CENPF, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_NUCLEAR_DIVISION, PAL_PRMT5_TARGETS_UP, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOBP_CHROMOSOME_LOCALIZATION

GO Biological Process (12): spindle organization (GO:0007051), mitotic spindle organization (GO:0007052), chromosome segregation (GO:0007059), mitotic spindle assembly checkpoint signaling (GO:0007094), positive regulation of cell population proliferation (GO:0008284), meiotic spindle assembly checkpoint signaling (GO:0033316), protein localization to kinetochore (GO:0034501), positive regulation of SMAD protein signal transduction (GO:0060391), repair of mitotic kinetochore microtubule attachment defect (GO:0140273), nuclear division (GO:0000280), protein phosphorylation (GO:0006468), nuclear chromosome segregation (GO:0098813)

GO Molecular Function (11): protein serine/threonine kinase activity (GO:0004674), protein serine/threonine/tyrosine kinase activity (GO:0004712), protein tyrosine kinase activity (GO:0004713), ATP binding (GO:0005524), identical protein binding (GO:0042802), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): kinetochore (GO:0000776), nucleus (GO:0005634), cytoplasm (GO:0005737), spindle (GO:0005819), membrane (GO:0016020)

GO top-level categories

46 GO namespaces:

Category	Terms
protein kinase activity	4
cell cycle process	2
mitotic cell cycle	2
spindle assembly checkpoint signaling	2
intracellular membraneless organelle	2
cellular anatomical structure	2
microtubule cytoskeleton organization	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
negative regulation of mitotic metaphase/anaphase transition	1
mitotic spindle checkpoint signaling	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
meiotic spindle checkpoint signaling	1
meiotic cell cycle	1
protein localization to chromosome, centromeric region	1
protein localization to condensed chromosome	1
regulation of SMAD protein signal transduction	1
SMAD protein signal transduction	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of intracellular signal transduction	1
mitotic metaphase chromosome alignment	1
repair of kinetochore microtubule attachment defect	1
mitotic cell cycle process	1
organelle fission	1
phosphorylation	1
protein modification process	1
chromosome segregation	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
condensed chromosome, centromeric region	1
supramolecular complex	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
microtubule cytoskeleton	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 28 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
mitotic spindle assembly checkpoint signaling	BP	direct assay
repair of mitotic kinetochore microtubule attachment defect	BP	direct assay
cytoplasm	CC	direct assay
membrane	CC	high-throughput assay
protein serine/threonine kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,828 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTK	BUB1	O43683	950
TTK	BUB3	O43684	876
TTK	MAD2L1	Q13257	864
TTK	BUB1B	O60566	858
TTK	CDC20	Q12834	802
TTK	TUBGCP3	Q96CW5	789
TTK	CENPE	Q02224	777
TTK	FANCM	Q8IYD8	759
TTK	CARMIL2	Q6F5E8	757
TTK	TMOD4	Q9NZQ9	717
TTK	PHC1	P78364	716
TTK	TMOD2	Q9NZR1	712
TTK	NDC80	O14777	660
TTK	NUF2	Q9BZD4	646
TTK	MAD2L2	Q9UI95	635

IntAct

Human interaction partners of TTK in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

11 partners by confidence:

Partner	Interaction type	MIscore	Records
TACC2	physical association	0.460	2
CDCA8	phosphorylation reaction	0.440	1
LRRK2	direct interaction	0.440	1
PRB3	physical association	0.400	1
RCBTB2	physical association	0.400	1
TGM1	physical association	0.400	1
TUBB	physical association	0.400	1
XIRP2	physical association	0.400	1
MAPK6	physical association	0.370	1
RPS6KA1	physical association	0.370	1
IBTK	association	0.350	1

BioGRID (221 interactions; top human partners by supporting records): CDC27 (Affinity Capture-Western; 4 records), SLC39A9 (Affinity Capture-MS; 3 records), SQSTM1 (Proximity Label-MS; 3 records), TP53 (Affinity Capture-Western; 3 records), APLNR (Affinity Capture-MS; 2 records), C1orf85 (Affinity Capture-MS; 2 records), C5AR2 (Affinity Capture-MS; 2 records), CENPJ (Proximity Label-MS; 2 records), CEP135 (Proximity Label-MS; 2 records), CHRM4 (Affinity Capture-MS; 2 records), FAM174A (Affinity Capture-MS; 2 records), FGFR1 (Proximity Label-MS; 2 records), FZR1 (Affinity Capture-Western; 2 records), GRPR (Affinity Capture-MS; 2 records), HSP90AA1 (Biochemical Activity; 2 records)

SIGNOR signaling

showing 25 of 64 signaling interactions:

A	Effect	B	Mechanism
TTK	up-regulates	CHEK2	phosphorylation
TTK	up-regulates	HSPA9	phosphorylation
TTK	up-regulates	CDCA8	phosphorylation
TTK	up-regulates	TTK	phosphorylation
TTK	down-regulates	TTK	phosphorylation
TTK	down-regulates	ABL1	phosphorylation
CHEK2	unknown	TTK	phosphorylation
TTK	up-regulates	TP53	phosphorylation
1124329-14-1	down-regulates	TTK	“chemical inhibition”
DNA_damage	up-regulates	TTK
CHEK2	up-regulates	TTK	phosphorylation
TTK	“down-regulates quantity by destabilization”	USP16	phosphorylation
TTK	“down-regulates quantity by destabilization”	MAP4	phosphorylation
PLK1	“up-regulates activity”	TTK	phosphorylation
TTK	“up-regulates activity”	BUB1	phosphorylation
TTK	“up-regulates activity”	CENPE	phosphorylation
TTK	“up-regulates activity”	MAPT	phosphorylation
TTK	“up-regulates activity”	MDM2	phosphorylation
TTK	“down-regulates activity”	ARHGEF17	phosphorylation
CDK2	“up-regulates quantity by stabilization”	TTK	phosphorylation
TTK	“up-regulates activity”	BLM	phosphorylation
TTK	“up-regulates activity”	NT5E	phosphorylation
CDR2	“up-regulates quantity by expression”	TTK	“transcriptional regulation”
TTK	“up-regulates activity”	MAD2L1	phosphorylation
TTK	“up-regulates activity”	TTK	phosphorylation

Disease & clinical

Genetic variants

Variant evidence for TTK: 136 ClinVar records (1 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

136 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	99
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2685207	GRCh37/hg19 6q14.1(chr6:79199356-80915988)x1	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore TTK’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 1,672):

Position(s)	Effect	Δscore	Sites
6:80005840	acceptor_loss	1.0000
6:80005983–80005984	donor_loss	1.0000	2
6:80008032–80008033	donor_loss	1.0000	3
6:80010808	acceptor_gain	1.0000
6:80010812–80010813	acceptor_loss	1.0000	5
6:80010958–80010959	donor_loss	1.0000	5
6:80011722	acceptor_gain	1.0000
6:80011727–80011728	acceptor_loss	1.0000	6
6:80011802–80011803	donor_loss	1.0000	3
6:80013269	acceptor_gain	1.0000

AlphaMissense

1,220 missense substitutions predicted likely pathogenic (of 5,702 scored), across 328 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M631	9	0.907	0.991
M690	9	0.865	0.986
D664	8	0.999	1.000
D647	8	0.995	0.999
D716	8	0.990	0.995
H645	8	0.989	0.997
F665	8	0.989	0.997
N652	8	0.982	0.999
F653	8	0.976	0.999
H639	8	0.975	0.996
F734	8	0.965	0.997
D608	8	0.952	0.977
W718	7	0.996	1.000
E571	7	0.994	0.998
K553	7	0.992	1.000
R779	7	0.986	0.998
K649	7	0.979	0.998
W628	7	0.977	0.999
E603	7	0.973	0.993
M602	7	0.966	0.994

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

9 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	5.17e-11
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	4.97e-08
Liver Hepatocellular Carcinoma (validation)	unfavorable	3.11e-07
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	1.96e-05
Kidney Chromophobe (TCGA)	unfavorable	4.12e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	8.1e-05
Lung Adenocarcinoma (TCGA)	unfavorable	9.06e-05
Uterine Corpus Endometrial Carcinoma (TCGA)	unfavorable	0.000553
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000611

Disease associations

OMIM: gene MIM:604092 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST006976_43	Macular thickness	6e-10
GCST003518_20	Daytime sleep phenotypes	4e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007828	daytime rest measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3983 (SINGLE PROTEIN), CHEMBL6177901 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193796 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the TTK protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
BAY-1161909	Small molecule	2
BAY-1217389	Small molecule	1

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 375,443 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

36 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1289926	AXITINIB	4	16,510
CHEMBL553	ERLOTINIB	4	109,860
CHEMBL1287853	FEDRATINIB	4	3,770
CHEMBL12856	INAMRINONE	4	9,739
CHEMBL608533	MIDOSTAURIN	4	7,641
CHEMBL502835	NINTEDANIB	4	8,978
CHEMBL477772	PAZOPANIB	4	16,241
CHEMBL1946170	REGORAFENIB	4	13,318
CHEMBL1789941	RUXOLITINIB	4	12,161
CHEMBL1336	SORAFENIB	4	87,476
CHEMBL535	SUNITINIB	4	80,232
CHEMBL3904602	LEROCICLIB	3	1,068
CHEMBL603469	LESTAURTINIB	3
CHEMBL4303241	BAY-1161909	2	50
CHEMBL513909	BI-2536	2	932
CHEMBL402548	DANUSERTIB	2	2,036
CHEMBL215152	DEFOSBARASERTIB	2	381
CHEMBL103667	DORAMAPIMOD	2	1,746
CHEMBL1230609	FORETINIB	2	3,230
CHEMBL4469414	LUVIXASERTIB	2	74
CHEMBL521851	PICTILISIB	2
CHEMBL475251	R-406	2
CHEMBL1738757	REBASTINIB	2
CHEMBL384304	RG-547	2
CHEMBL14762	SELICICLIB	2
CHEMBL1721885	SU-014813	2
CHEMBL230011	TG100-115	2
CHEMBL572878	TOZASERTIB	2
CHEMBL4456085	BAY-1217389	1
CHEMBL574738	AST-487	1
CHEMBL4439259	AZD-7648	1
CHEMBL3924132	BOS-172722	1
CHEMBL482967	CYC-116	1
CHEMBL3122113	DNL-201	1
CHEMBL1908397	KW-2449	1
CHEMBL259084	MLN-8054	1

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — TTK family

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
compound 20 [PMID: 30998356]	Inhibition	9.15	pIC50
luvixasertib	Inhibition	8.77	pIC50
MPI-0479605	Inhibition	8.74	pIC50
compound 27f [PMID: 25625617]	Inhibition	8.55	pIC50
compound 34h [PMID: 27055065]	Inhibition	8.3	pIC50
BAY1217389	Inhibition	8.0	pIC50
empesertib	Inhibition	8.0	pIC50
BOS172722	Inhibition	7.96	pIC50
AZ3146	Inhibition	7.46	pIC50
Ro3280	Inhibition	7.29	pKd
GNE-7915	Inhibition	7.28	pKi
NMS-P715	Inhibition	6.74	pIC50
MPS1-IN-1	Inhibition	6.44	pIC50

Binding affinities (BindingDB)

1336 measured of 1811 human assays (1813 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(4-fluorophenyl)-N-[4-[2-[2-methoxy-4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)anilino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]acetamide	IC50	0.1 nM	US-9555022: Substituted triazolopyridines
CHEMBL5180090	IC50	0.12 nM
CHEMBL5194436	IC50	0.13 nM
2-(4-fluorophenyl)-N-[4-[2-[2-methoxy-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]anilino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]acetamide	IC50	0.15 nM	US-9555022: Substituted triazolopyridines
2-(4-fluorophenyl)-N-[4-[2-[4-(morpholine-4-carbonyl)-2-(2,2,2-trifluoroethoxy)anilino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]acetamide	IC50	0.2 nM	US-9555022: Substituted triazolopyridines
N-cyclopropyl-2-methyl-4-[6-pyridin-4-yl-4-(3,3,3-trifluoropropylamino)benzimidazol-1-yl]benzamide	IC50	0.2 nM	US-9388140: Substituted benzimidazoles
N-cyclopropyl-4-[6-(2,3-difluorophenoxy)-4-(oxan-4-ylmethylamino)benzimidazol-1-yl]-2-methylbenzamide	IC50	0.2 nM	US-9388140: Substituted benzimidazoles
N-cyclopropyl-4-[6-(2-hydroxyphenoxy)-4-(3,3,3-trifluoropropylamino)benzimidazol-1-yl]-2-methylbenzamide	IC50	0.2 nM	US-9388140: Substituted benzimidazoles
N-cyclopropyl-4-[6-[(3-fluoro-2-hydroxyphenyl)-hydroxymethyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.2 nM	US-9512126: Substituted imidazopyridazines
CHEMBL4642174	IC50	0.2 nM
CHEMBL4846040	KD	0.2 nM
CHEMBL4546504	IC50	0.261 nM
CHEMBL4869527	KD	0.29 nM
4-[6-(2-hydroxyphenoxy)-4-(3,3,3-trifluoropropylamino)benzimidazol-1-yl]-N,2-dimethylbenzamide	IC50	0.3 nM	US-9388140: Substituted benzimidazoles
N-cyclopropyl-4-[6-[1-(3-fluoro-4-methoxyphenyl)ethenyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.3 nM	US-9512126: Substituted imidazopyridazines
N-cyclopropyl-4-[6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.3 nM	US-9512126: Substituted imidazopyridazines
N-cyclopropyl-4-[6-[(2,5-difluorophenyl)-hydroxymethyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.3 nM	US-9512126: Substituted imidazopyridazines
N-cyclopropyl-4-[6-[1-(3-fluorophenyl)ethenyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.3 nM	US-9512126: Substituted imidazopyridazines
CHEMBL3354568	IC50	0.3 nM
CHEMBL3410078	IC50	0.3 nM
CHEMBL4645348	IC50	0.3 nM
CHEMBL4868353	KD	0.3 nM
CHEMBL4555040	IC50	0.316 nM
(2R)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propanamide	IC50	0.34 nM
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
N-cyclopropyl-4-[6-(3-fluorophenoxy)-4-(oxan-4-ylmethylamino)benzimidazol-1-yl]-2-methylbenzamide	IC50	0.4 nM	US-9388140: Substituted benzimidazoles
BDBM236695	IC50	0.4 nM	US-9388140: Substituted benzimidazoles
BDBM236703	IC50	0.4 nM	US-9388140: Substituted benzimidazoles
N-cyclopropyl-4-[6-(3-fluoro-4-methoxyphenoxy)-4-(3,3,3-trifluoropropylamino)benzimidazol-1-yl]benzamide	IC50	0.4 nM	US-9388140: Substituted benzimidazoles
N-cyclopropyl-4-[6-(3-fluoro-2-hydroxyphenoxy)-4-(3,3,3-trifluoropropylamino)benzimidazol-1-yl]-2-methylbenzamide	IC50	0.4 nM	US-9388140: Substituted benzimidazoles
N-cyclopropyl-4-[6-[1-(2,3-difluorophenyl)ethenyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.4 nM	US-9512126: Substituted imidazopyridazines
N-cyclopropyl-4-[6-[1-(5-fluoro-2-hydroxyphenyl)ethenyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.4 nM	US-9512126: Substituted imidazopyridazines
N-cyclopropyl-4-[6-(3-fluoro-4-methoxybenzoyl)-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.4 nM	US-9512126: Substituted imidazopyridazines
CHEMBL4640247	IC50	0.4 nM
CHEMBL4860430	KD	0.41 nM
CHEMBL4866294	KD	0.41 nM
JDM697A	IC50	0.41 nM	US-11208696: Prognostic biomarkers for TTK inhibitor chemotherapy
JDM666A	IC50	0.41 nM	US-11208696: Prognostic biomarkers for TTK inhibitor chemotherapy
JDM0684A	IC50	0.43 nM	US-11208696: Prognostic biomarkers for TTK inhibitor chemotherapy
JDM703A	IC50	0.43 nM	US-11208696: Prognostic biomarkers for TTK inhibitor chemotherapy
N-(2,6-diethylphenyl)-8-(2-methoxy-4-piperazin-1-yl-anilino)-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide	IC50	0.49 nM	US-11208696: Prognostic biomarkers for TTK inhibitor chemotherapy
N-cyclopropyl-2-methyl-4-[6-phenoxy-4-(3,3,3-trifluoropropylamino)benzimidazol-1-yl]benzamide	IC50	0.5 nM	US-9388140: Substituted benzimidazoles
N-cyclopropyl-4-[6-(3-methoxybenzoyl)-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.5 nM	US-9512126: Substituted imidazopyridazines
N-cyclopropyl-4-[6-[1-(4-methoxyphenyl)ethenyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.5 nM	US-9512126: Substituted imidazopyridazines
N-cyclopropyl-4-[6-[(2,5-difluorophenyl)-difluoromethyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	IC50	0.5 nM	US-9512126: Substituted imidazopyridazines
(2R)—N-{4-[2-({4-[(3-fluoroazetidin-1-yl)carbonyl]-2-methoxyphenyl}amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl}-2-(4-fluorophenyl)propanamide	IC50	0.5 nM
US10399974, Example 1	IC50	0.5 nM	US-10399974: N2-phenyl-pyrido[3,4-D]pyrimidine-2, 8-diamine derivatives and their use as Mps1 inhibitors
CHEMBL4634949	IC50	0.5 nM
CHEMBL4867504	KD	0.5 nM
CHEMBL4873395	KD	0.56 nM

ChEMBL bioactivities

2238 potent at pChembl≥5 of 2282 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.33	Ki	0.047	nM	CHEMBL4249882
10.15	Kd	0.071	nM	CHEMBL4877547
10.08	Ki	0.084	nM	CHEMBL3911532
10.06	Ki	0.088	nM	CHEMBL4245639
10.03	Ki	0.094	nM	CHEMBL3927553
10.00	Ki	0.1	nM	LUVIXASERTIB
10.00	IC50	0.1	nM	CHEMBL4632740
9.96	Ki	0.11	nM	CHEMBL4239476
9.96	Ki	0.11	nM	BOS-172722
9.92	Ki	0.12	nM	CHEMBL4247121
9.92	Ki	0.12	nM	CHEMBL4240502
9.92	Kd	0.12	nM	CHEMBL4845775
9.89	Ki	0.13	nM	CHEMBL3932996
9.82	IC50	0.15	nM	CHEMBL4636046
9.82	Kd	0.15	nM	CHEMBL4875028
9.77	Kd	0.17	nM	CHEMBL4870223
9.77	Kd	0.17	nM	CHEMBL4858486
9.72	Ki	0.19	nM	CHEMBL4251352
9.70	Ki	0.2	nM	CHEMBL3809829
9.70	IC50	0.2	nM	CHEMBL3951371
9.70	IC50	0.2	nM	CHEMBL3928754
9.70	IC50	0.2	nM	CHEMBL3961628
9.70	Ki	0.2	nM	CHEMBL4249151
9.70	IC50	0.2	nM	CHEMBL4638914
9.70	IC50	0.2	nM	CHEMBL4642174
9.70	Kd	0.2	nM	CHEMBL4846040
9.60	IC50	0.25	nM	BAY-1217389
9.54	Kd	0.29	nM	CHEMBL4869527
9.52	IC50	0.3	nM	CHEMBL3354568
9.52	IC50	0.3	nM	CHEMBL3410078
9.52	IC50	0.3	nM	CHEMBL3965128
9.52	IC50	0.3	nM	CHEMBL4632416
9.52	IC50	0.3	nM	CHEMBL4645348
9.52	Kd	0.3	nM	CHEMBL4868353
9.47	IC50	0.34	nM	BAY-1161909
9.42	Ki	0.38	nM	CHEMBL4250961
9.40	IC50	0.4	nM	CHEMBL3354567
9.40	IC50	0.4	nM	CHEMBL3818646
9.40	IC50	0.4	nM	CHEMBL3932181
9.40	IC50	0.4	nM	CHEMBL3912382
9.40	IC50	0.4	nM	CHEMBL3941964
9.40	IC50	0.4	nM	CHEMBL3923628
9.40	IC50	0.4	nM	CHEMBL3918586
9.40	IC50	0.4	nM	CHEMBL4640247
9.39	Kd	0.41	nM	CHEMBL4860430
9.39	Kd	0.41	nM	CHEMBL4866294
9.39	IC50	0.41	nM	CHEMBL5830301
9.39	IC50	0.41	nM	CHEMBL6018982
9.37	IC50	0.43	nM	CHEMBL5401292
9.37	IC50	0.43	nM	CHEMBL5801593

PubChem BioAssay actives

964 with measured affinity, of 1766 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
8-N-[(2S)-3,3-dimethylbutan-2-yl]-2-N-[2-ethoxy-4-(4-methyl-1,2,4-triazol-3-yl)phenyl]-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	<0.0001	uM
N-cyclopropyl-4-[7-[(3-hydroxy-3-methylcyclobutyl)methylamino]-5-pyridin-3-yloxypyrazolo[1,5-a]pyrimidin-3-yl]-2-methylbenzamide	1627435: Inhibition of full length recombinant N-terminal GST-tagged and sumo-tagged human TTK (1 to 275 residues) expressed in Escherichia coli pre-incubated for 5 mins before ATP addition by indirect ELISA	ki	0.0001	uM
N-[2-ethoxy-4-(4-methyl-1,2,4-triazol-3-yl)phenyl]-6-methyl-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0001	uM
8-(3,3-dimethylazetidin-1-yl)-N-[2-ethoxy-4-(4-methyl-1,2,4-triazol-3-yl)phenyl]-6-methylpyrido[3,4-d]pyrimidin-2-amine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0001	uM
8-N-(2,2-dimethylpropyl)-2-N-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)-2-ethoxyphenyl]-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0001	uM
2-N-[4-[5-[2-(dimethylamino)ethyl]-4-methyl-1,2,4-triazol-3-yl]-2-ethoxyphenyl]-8-N-(2,2-dimethylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0001	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]cyclopentanecarboxamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0001	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]cyclohexanecarboxamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0001	uM
N-cyclopropyl-4-[7-[2-(3-hydroxy-3-methylcyclobutyl)ethyl]-5-pyridin-3-yloxypyrazolo[1,5-a]pyrimidin-3-yl]-2-methylbenzamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0001	uM
2-(4-fluorophenyl)-N-[4-[2-[2-methoxy-4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)anilino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]acetamide	1660100: Inhibition of GST-tagged recombinant human MPS1 expressed in baculovirus expression system using biotin-Ahx-PWDPDDADITEILG as substrate preincubated for 15 mins followed by substrate and 2 mM ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0001	uM
2-(4-fluorophenyl)-N-[4-[2-[2-methoxy-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]anilino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]acetamide	1660100: Inhibition of GST-tagged recombinant human MPS1 expressed in baculovirus expression system using biotin-Ahx-PWDPDDADITEILG as substrate preincubated for 15 mins followed by substrate and 2 mM ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0001	uM
8-N-(2,2-dimethylpropyl)-2-N-[2-ethoxy-4-(4-methyl-1,2,4-triazol-3-yl)phenyl]-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0001	uM
2-N-[4-(2,3-dimethylimidazol-4-yl)-2-methoxyphenyl]-8-N-(2,2-dimethylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0001	uM
8-N-(2,2-dimethylpropyl)-2-N-[2-methoxy-4-(4-methyl-1,2,4-triazol-3-yl)phenyl]-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0001	uM
2-N-[4-(2,3-dimethylimidazol-4-yl)-2-methoxyphenyl]-8-N-(2,2-dimethylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0001	uM
1-[2-[2-ethoxy-4-(4-methyl-1,2,4-triazol-3-yl)anilino]-6-methylpyrido[3,4-d]pyrimidin-8-yl]-3-methylazetidine-3-carbonitrile	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0002	uM
2-N-[4-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methoxyphenyl]-8-N-(2,2-dimethylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0002	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]-2,2-dimethylpropanamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0002	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-6-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]cyclohexanecarboxamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0002	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-6-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]cyclopentanecarboxamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0002	uM
2-(4-fluorophenyl)-N-[4-[2-[4-(morpholine-4-carbonyl)-2-(2,2,2-trifluoroethoxy)anilino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]acetamide	1660100: Inhibition of GST-tagged recombinant human MPS1 expressed in baculovirus expression system using biotin-Ahx-PWDPDDADITEILG as substrate preincubated for 15 mins followed by substrate and 2 mM ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0002	uM
4-[6-benzyl-8-(3,3,3-trifluoropropylamino)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropyl-2-methylbenzamide	1660099: Inhibition of GST-tagged recombinant human MPS1 expressed in baculovirus expression system using biotin-Ahx-PWDPDDADITEILG as substrate preincubated for 15 mins followed by substrate and 10 uM ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0002	uM
8-N-[(2S)-3,3-dimethylbutan-2-yl]-2-N-[2-methoxy-4-(1-methylpyrazol-4-yl)phenyl]pyrido[3,4-d]pyrimidine-2,8-diamine	1302308: Inhibition of human full length MPS1 expressed in recombinant baculovirus infected Sf9 insect cells using 5FAM-DHTGFLTEYVATRCONH2 as substrate after 60 to 90 mins in presence of 1 mM ATP	ki	0.0002	uM
N-cyclopropyl-4-[6-(2-hydroxyphenoxy)-8-(oxan-4-ylmethylamino)imidazo[1,2-b]pyridazin-3-yl]benzamide	1197787: Inhibition of FLAG-tagged Mps1 autophosphorylation in human RERF-LC-AI cells expressing Tet-suppressible promotor after 3 hrs by immunoblotting	ic50	0.0003	uM
N-cyclopropyl-4-[8-[(3-hydroxy-3-methylcyclobutyl)methylamino]-6-pyridin-3-yloxyimidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	1660100: Inhibition of GST-tagged recombinant human MPS1 expressed in baculovirus expression system using biotin-Ahx-PWDPDDADITEILG as substrate preincubated for 15 mins followed by substrate and 2 mM ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0003	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]benzamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0003	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-6-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]propanamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0003	uM
(2R)-2-(4-fluorophenyl)-N-[4-[2-(2-methoxy-4-methylsulfonylanilino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]propanamide	1552062: Inhibition of MPS1 (unknown origin) using biotin-AhxPWDPDDADITEILG-NH2 as substrate preincubated for 15 mins followed by substrate addition by TR-FRET assay	ic50	0.0003	uM
N-cyclopropyl-4-[6-[1-(3-fluoro-4-methoxyphenyl)ethenyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	1660101: Inhibition of MPS1 in human HeLa cells assessed as reduction in spindle assembly checkpoint incubated for 4 hrs by p-histone H3/Hoechst 33342 staining based microscopic analysis	ic50	0.0003	uM
N-cyclopropyl-4-[6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	1177105: Inhibition of Mps1 (unknown origin) activity by TR-FRET assay	ic50	0.0003	uM
N-cyclopropyl-4-[6-(2,3-difluoro-4-methoxyphenoxy)-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	1660101: Inhibition of MPS1 in human HeLa cells assessed as reduction in spindle assembly checkpoint incubated for 4 hrs by p-histone H3/Hoechst 33342 staining based microscopic analysis	ic50	0.0003	uM
2-N-[4-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-ethoxyphenyl]-8-N-(2,2-dimethylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0004	uM
N-cyclopropyl-4-[5-(2,3-difluoro-4-methoxyphenoxy)-7-(3,3,3-trifluoropropylamino)pyrazolo[1,5-a]pyrimidin-3-yl]-2-methylbenzamide	1660101: Inhibition of MPS1 in human HeLa cells assessed as reduction in spindle assembly checkpoint incubated for 4 hrs by p-histone H3/Hoechst 33342 staining based microscopic analysis	ic50	0.0004	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]cyclopropanecarboxamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0004	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]propanamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0004	uM
N-cyclopropyl-4-[6-(3-fluoro-4-methoxybenzoyl)-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	1177105: Inhibition of Mps1 (unknown origin) activity by TR-FRET assay	ic50	0.0004	uM
8-N-(2,2-dimethylpropyl)-2-N-[2-methoxy-4-(1-methylpyrazol-4-yl)phenyl]pyrido[3,4-d]pyrimidine-2,8-diamine	1400289: Inhibition of full length human N-terminal 6xHis-tagged MPS1 expressed in baculovirus expression system using 5FAM-H236 peptide as substrate after 60 to 90 mins by caliper assay	ki	0.0004	uM
N-cyclopropyl-4-[2-(2,3-difluorophenoxy)-4-(oxan-4-ylmethylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl]-2-methylbenzamide	1309251: Inhibition of TTK (unknown origin)	ic50	0.0004	uM
4-[(1-hydroxy-2-methylpropan-2-yl)amino]-2-[(2-methyl-6-morpholin-4-yl-3-pyridinyl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile	1552063: Inhibition of MPS1 (510 to 857 residues) catalytic domain (unknown origin) expressed in Escherichia coli after 15 mins by mass-spectrometry analysis	ki	0.0005	uM
2-[(2-methyl-6-morpholin-4-yl-3-pyridinyl)amino]-4-(oxan-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile	1552063: Inhibition of MPS1 (510 to 857 residues) catalytic domain (unknown origin) expressed in Escherichia coli after 15 mins by mass-spectrometry analysis	ki	0.0005	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]-2-methylpropanamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0005	uM
N-cyclopropyl-2-methyl-4-[6-phenoxy-8-(3,3,3-trifluoropropylamino)imidazo[1,2-a]pyrazin-3-yl]benzamide	1660099: Inhibition of GST-tagged recombinant human MPS1 expressed in baculovirus expression system using biotin-Ahx-PWDPDDADITEILG as substrate preincubated for 15 mins followed by substrate and 10 uM ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0005	uM
(2R)-N-[4-[2-[4-(3-fluoroazetidine-1-carbonyl)-2-methoxyanilino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]-2-(4-fluorophenyl)propanamide	1660100: Inhibition of GST-tagged recombinant human MPS1 expressed in baculovirus expression system using biotin-Ahx-PWDPDDADITEILG as substrate preincubated for 15 mins followed by substrate and 2 mM ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0005	uM
N-(2,6-diethylphenyl)-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide	1924156: Inhibition of human TTK by TR-FRET assay	ic50	0.0006	uM
4-[[4-(4-hydroxy-4-methylcyclohexyl)oxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N,N-dimethylbenzamide	1551587: Inhibition of Kinase Tracer 236 binding to recombinant human full-length GST-tagged TTk expressed in baculovirus expression system measured after 1 hr by LanthaScreen Eu–kinase binding assay	ic50	0.0006	uM
N-[4-[2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]adamantane-1-carboxamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0006	uM
N-[4-[5-methyl-2-[2-methyl-4-(4-methylpiperazin-1-yl)anilino]-7-oxopyrido[2,3-d]pyrimidin-8-yl]cyclohexyl]propanamide	1760717: Binding affinity to wild-type human partial length TTK (N505 to V798 residues) expressed in bacterial expression system by active site-directed competition binding based Kinomescan method	kd	0.0006	uM
N-cyclopropyl-4-[6-[difluoro-(4-methoxyphenyl)methyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	1177105: Inhibition of Mps1 (unknown origin) activity by TR-FRET assay	ic50	0.0006	uM
N-cyclopropyl-4-[6-[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]-8-(3,3,3-trifluoropropylamino)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide	1660099: Inhibition of GST-tagged recombinant human MPS1 expressed in baculovirus expression system using biotin-Ahx-PWDPDDADITEILG as substrate preincubated for 15 mins followed by substrate and 10 uM ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0006	uM
N-[(R)-cyclopropyl(pyridin-2-yl)methyl]-3-[4-[(1S,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl]phenyl]-1H-indazole-5-carboxamide	1203320: Competitive inhibition of amino terminal GST-fused full length human TTK using His6-SUMO-TTK-N as substrate by Lineweaver-Burk plot analysis in presence of ATP	ki	0.0007	uM

CTD chemical–gene interactions

96 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	5
Acetaminophen	decreases expression, increases expression	3
Estradiol	increases expression	3
Valproic Acid	decreases expression	3
bisphenol A	decreases expression, decreases methylation	2
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
Resveratrol	decreases expression, affects cotreatment, increases expression	2
Testosterone	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
propionaldehyde	decreases expression	1
deoxynivalenol	increases expression	1
geraniol	decreases expression	1
methylselenic acid	decreases expression	1
kojic acid	decreases expression	1
beta-lapachone	decreases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
cryptolepine	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
diallyl trisulfide	decreases expression	1
beta-methylcholine	affects expression	1

ChEMBL screening assays

505 unique, capped per target: 473 binding, 32 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1021461	Binding	Inhibition of TTK assessed as enzyme activity relative to control	Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). — *J Med Chem*
CHEMBL5444952	Functional	Affinity Phenotypic Cellular interaction: (Immunoblot activity assay (using LAP-Mps1 WT in U2OS cells)) EUB0000608a TTK	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomic Library

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TTK across ~30M SureChEMBL compounds — explore on Sugi Predict.