PTK6

Summary

PTK6 (protein tyrosine kinase 6, HGNC:9617) is a protein-coding gene on chromosome 20q13.33, encoding Protein-tyrosine kinase 6 (Q13882). Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth.

The protein encoded by this gene is a cytoplasmic nonreceptor protein kinase which may function as an intracellular signal transducer in epithelial tissues. Overexpression of this gene in mammary epithelial cells leads to sensitization of the cells to epidermal growth factor and results in a partially transformed phenotype. Expression of this gene has been detected at low levels in some breast tumors but not in normal breast tissue. The encoded protein has been shown to undergo autophosphorylation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5753 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 92 total
• Phenotypes (HPO): 1
• Druggable target: yes — 43 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_005975

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9617
Approved symbol	PTK6
Name	protein tyrosine kinase 6
Location	20q13.33
Locus type	gene with protein product
Status	Approved
Aliases	BRK
Ensembl gene	ENSG00000101213
Ensembl biotype	protein_coding
OMIM	602004
Entrez	5753

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000217185, ENST00000542869, ENST00000853329, ENST00000957005, ENST00000957006, ENST00000957007

RefSeq mRNA: 2 — MANE Select: NM_005975 NM_001256358, NM_005975

CCDS: CCDS13524, CCDS74750

Canonical transcript exons

ENST00000542869 — 8 exons

Exon	Start	End
ENSE00000663476	63534938	63535059
ENSE00001173533	63537085	63537376
ENSE00002296949	63528001	63529723
ENSE00003716422	63534152	63534315
ENSE00003721824	63530746	63530927
ENSE00003736011	63530078	63530231
ENSE00003740279	63533551	63533704
ENSE00003754776	63532526	63532687

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 97.88.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9025 / max 47.4965, expressed in 279 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188381	0.6067	206
188382	0.2958	164

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	97.88	gold quality
lower esophagus mucosa	UBERON:0035834	97.84	gold quality
epithelium of esophagus	UBERON:0001976	96.65	gold quality
esophagus mucosa	UBERON:0002469	95.76	gold quality
mucosa of transverse colon	UBERON:0004991	95.41	gold quality
squamous epithelium	UBERON:0006914	94.56	gold quality
penis	UBERON:0000989	92.84	gold quality
cervix squamous epithelium	UBERON:0006922	92.57	gold quality
skin of abdomen	UBERON:0001416	92.14	gold quality
skin of leg	UBERON:0001511	92.03	gold quality
pharyngeal mucosa	UBERON:0000355	91.35	gold quality
zone of skin	UBERON:0000014	91.03	gold quality
gingiva	UBERON:0001828	90.88	gold quality
amniotic fluid	UBERON:0000173	90.78	gold quality
gingival epithelium	UBERON:0001949	90.63	gold quality
oral cavity	UBERON:0000167	90.62	gold quality
jejunal mucosa	UBERON:0000399	89.92	gold quality
cervix epithelium	UBERON:0004801	88.85	gold quality
colonic mucosa	UBERON:0000317	87.49	gold quality
upper arm skin	UBERON:0004263	87.45	gold quality
buccal mucosa cell	CL:0002336	87.16	gold quality
duodenum	UBERON:0002114	87.11	gold quality
mammalian vulva	UBERON:0000997	86.87	gold quality
vagina	UBERON:0000996	85.97	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.71	gold quality
transverse colon	UBERON:0001157	85.51	gold quality
tongue squamous epithelium	UBERON:0006919	85.20	gold quality
upper leg skin	UBERON:0004262	84.66	gold quality
rectum	UBERON:0001052	83.72	gold quality
ileal mucosa	UBERON:0000331	83.57	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EPAS1, HIF1A, HNF4A, MYC, SP1, STAT3, TXK, ZNF91

miRNA regulators (miRDB)

62 targeting PTK6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-3678-3P	99.31	67.10	1432
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-7151-3P	99.04	69.72	2370

Literature-anchored findings (GeneRIF, showing 40)

• the effect of Sam68 was inhibited in a dose-dependent manner by coexpression of an activated form of the nuclear kinase Sik/BRK that hyperphosphorylated Sam68 (PMID:12482964)
• The tyrosine kinases Brk/PTK6/Sik, Srm, Frk/Rak/Gtk/Iyk/Bsk, and Src42A/Dsrc41 have a low degree of sequence homology to other known kinases. The exon structure of these kinases, called the Brk family, is highly conserved and distinct. (PMID:12725532)
• BRK plays a role in differentiation of prostate epithelial cells (PMID:12833144)
• Study suggests that SH3 interactions will govern phosphorylation of many substrates by BRK. (PMID:14676834)
• Results describe the solution structure and backbone dynamics of the human protein-tyrosine kinase-6 Src homology 2 (SH2) domain using multidimensional NMR spectroscopy. (PMID:15056653)
• in breast cancer cells breast tumor kinase (Brk) behaves similarly to a constitutively active Brk mutant (YF-Brk) and associates with tyrosine-phosphorylated proteins in deregulated signaling complexes (PMID:15539407)
• BRK activates rac1 and promotes cell migration and invasion by phosphorylating paxillin. (PMID:15572663)
• endogenous Brk and IRS-4 interact in A431 human epidermoid carcinoma cells (PMID:15870689)
• the interaction between SH2-kinase linker and kinase domain is essential for the catalytic activity of PTK6 (PMID:15961400)
• Sam68 suppresses BRK-induced cell proliferation, and regulates intranuclear localization and cell cycle progression (PMID:16179349)
• Identification of STAT3 as a specific substrate of breast tumor kinase. (PMID:16568091)
• Our results indicate that Brk may play a key role in lymphomagenesis, hence identifying the kinase as a potential therapeutic target in lymphomas. (PMID:16651629)
• Brk can directly phosphorylate STAT5b on Y699. Subsequently, this Brk-mediated STAT5b phosphorylation leads to STAT5b transcriptional activity, and this activity is further increased by kinase active c-Src. (PMID:17997837)
• These findings therefore reveal new substrates of BRK and define KAP3A as a physiological substrate of BRK during cell migration. (PMID:18077133)
• PTK6 is coamplified and coexpressed with ERBB2 in human breast cancers. ERBB2 interacts with PTK6 and increases its intrinsic kinase activity (PMID:18719096)
• PTK6 expression is of significant prognostic value in the outcome of breast carcinomas. In multivariate analysis, the disease-free survival of patients of >or=240 months was directly associated with the protein expression level of PTK6 (PMID:18781181)
• A previously unknown function of Brk in regulating both RhoA and Ras by phosphorylating p190 and a crucial role of this Brk-elicited signaling pathway in promoting breast malignancy. (PMID:18829532)
• PTK6 performs contrasting roles in tumorigenicity depending on its intracellular localization, displaying increased oncogenic abilities when targeted to the plasma membrane and decreased oncogenicity when targeted to the nucleus. (PMID:19304789)
• STAP-2 is phosphorylated at Tyr250 by Brk, and plays an important role in Brk-mediated STAT3 activation. (PMID:19393627)
• the structural basis of the SH3-Linker interaction that results in auto-inhibition of PTK6 was reported. (PMID:19401189)
• The breast tumor kinase SH3-domain interacted with N-terminal polyproline rich motifs of PTB-associated splicing factor and the PTB-associated splicing factor C-terminal tyrosines are the site of tyrosine phosphorylation by breast tumor kinase. (PMID:19439179)
• PTK6 overexpression is not essentially attributed to gene amplification, and the PTK6 protein expression-but not gene status-is of prognostic value in breast carcinomas. PTK6 protein overexpression may result from polysomy 20 in a minority of the tumors. (PMID:19621240)
• Brk enhances breast carcinoma cell survival in suspension, suggesting a role for Brk in supporting breast cancer cell dissemination (PMID:19661439)
• PTK6 associates with nuclear and cytoplasmic beta-catenin and inhibits beta-catenin- and T-cell factor (TCF)-mediated transcription. (PMID:20026641)
• Brk antagonizes the transcriptional activity of the transcription factor FoxO family of proteins by inhibiting its nuclear localization. As a result, the cell cycle inhibitor p27, a FoxO target gene, is down-regulated. (PMID:20162673)
• PTK6 enhances EGFR signaling by inhibition of EGFR down-regulation through phosphorylation of ARAP1 in breast cancer cells. (PMID:20554524)
• AKT is a direct substrate of PTK6 and AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. (PMID:20606012)
• Results identified Brk and ERK5 as important downstream effectors of Met signaling to cell migration. (PMID:20687930)
• Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells. (PMID:20929863)
• show that as primary human keratinocytes are induced to differentiate in vitro, Brk levels decrease (PMID:21240512)
• Data suggest that since PTK6 plays an important role in HER receptor signal transduction, its down-regulation might be suitable for future therapy approaches in breast cancer. (PMID:21380407)
• Alternative transcript-PTK6 is able to negatively regulate growth and modulate PTK6 activity, protein-protein associations and/or subcellular localization. (PMID:21479203)
• present findings indicate an increase of cytoplasmic Brk expression in non-small cell lung cancer (PMID:21603980)
• Brk expression in human breast tumors may contribute to progression by inducing p38-driven pro-survival signaling pathways. (PMID:21923922)
• a novel function for PTK6 at the plasma membrane (PMID:22084245)
• breast tumor kinase (Brk)/protein-tyrosine kinase 6 (PTK6), a nonreceptor protein-tyrosine kinase highly expressed in most human breast tumors, interacted with EGFR and sustained ligand-induced EGFR signaling. (PMID:22231447)
• Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3. (PMID:22547065)
• PTK6 was identified as a transcript that is down-regulated in human esophageal squamous cell carcinoma via epigenetic modification at the PTK6 locus. (PMID:22705009)
• results demonstrate that Hsp90 plays an essential role in regulating PTK6 stability and suggest that Hsp90 inhibitors may be useful as therapeutic drugs for PTK6-positive cancers, including breast cancer (PMID:22849407)
• Knockdown of PTK6 enhances apoptosis in HCT116 cells with wild-type p53. (PMID:22989419)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptk6a	ENSDARG00000017947
danio_rerio	ptk6b	ENSDARG00000059956
mus_musculus	Ptk6	ENSMUSG00000038751
rattus_norvegicus	Ptk6	ENSRNOG00000012987

Paralogs (32): FGR (ENSG00000000938), MATK (ENSG00000007264), BTK (ENSG00000010671), FYN (ENSG00000010810), STYK1 (ENSG00000060140), TNK2 (ENSG00000061938), TXK (ENSG00000074966), JAK2 (ENSG00000096968), ABL1 (ENSG00000097007), HCK (ENSG00000101336), BMX (ENSG00000102010), CSK (ENSG00000103653), TYK2 (ENSG00000105397), JAK3 (ENSG00000105639), FRK (ENSG00000111816), ITK (ENSG00000113263), ZAP70 (ENSG00000115085), PTK2B (ENSG00000120899), SRMS (ENSG00000125508), TEC (ENSG00000135605), BLK (ENSG00000136573), ABL2 (ENSG00000143322), FER (ENSG00000151422), JAK1 (ENSG00000162434), SYK (ENSG00000165025), PTK2 (ENSG00000169398), TNK1 (ENSG00000174292), YES1 (ENSG00000176105), FES (ENSG00000182511), LCK (ENSG00000182866), SRC (ENSG00000197122), LYN (ENSG00000254087)

Protein

Protein identifiers

Protein-tyrosine kinase 6 — Q13882 (reviewed: Q13882)

Alternative names: Breast tumor kinase, Tyrosine-protein kinase BRK

All UniProt accessions (1): Q13882

UniProt curated annotations — full annotation on UniProt →

Function. Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Phosphorylates the GTPase-activating protein ARAP1 following EGF stimulation which enhances EGFR signaling by delaying EGFR down-regulation. Also associates with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways. Inhibits PTK6 phosphorylation and PTK6 association with other tyrosine-phosphorylated proteins.

Subunit / interactions. Interacts with GAP-A.p65. Interacts (via SH3 and SH2 domains) with KHDRBS1. Interacts (via SH3 and SH2 domains) with phosphorylated IRS4. Interacts with ADAM15. Interacts (via SH3 domain) with SFPQ. Interacts with EGFR and ERBB2. Interacts with STAP2. Interacts with PNX. Interacts with SFPQ. Interacts with PTK/ATK. Interacts with CTNNB1.

Subcellular location. Cytoplasm. Nucleus. Cell projection. Ruffle. Membrane.

Tissue specificity. Epithelia-specific. Very high level in colon and high levels in small intestine and prostate, and low levels in some fetal tissues. Not expressed in breast or ovarian tissue but expressed in high percentage of breast and ovarian cancers. Also overexpressed in some metastatic melanomas, lymphomas, colon cancers, squamous cell carcinomas and prostate cancers. Also found in melanocytes. Not expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform 2 is present in prostate epithelial cell lines derived from normal prostate and prostate adenocarcinomas, as well as in a variety of cell lines.

Post-translational modifications. Autophosphorylated. Autophosphorylation of Tyr-342 leads to an increase of kinase activity. Tyr-447 binds to the SH2 domain when phosphorylated and negatively regulates kinase activity.

Activity regulation. Activated by EGF, NRG1 and IGF1. Inhibited by SOCS3 to phosphorylate STAT3. Stabilized in the inactive form by an association between the SH3 domain and the SH2-TK linker region. Interaction between Trp-184 within SH2-TK linker region and the catalytic domain appears essential for positive regulation of kinase activity.

Domain organisation. The SH3 domain plays a major role in substrate interactions. The SH2 domain of PTK6 plays a role in protein-protein interactions, but is likely more important for the regulation of catalytic activity.

Miscellaneous. The inhibitors bind to the ATP-binding pocket.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. BRK/PTK6/SIK subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13882-1	1	yes
Q13882-2	2, ALT-PTK6, LambdaM5

RefSeq proteins (2): NP_001243287, NP_005966* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000980	SH2	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001452	SH3_domain	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR035846	PTK6_SH2	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR050198	Non-receptor_tyrosine_kinases	Family

Pfam: PF00017, PF00018, PF07714

Enzyme classification (BRENDA):

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (73 total): strand 21, helix 19, mutagenesis site 9, modified residue 7, turn 5, domain 3, splice variant 2, sequence variant 2, binding site 2, chain 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6CZ4	X-RAY DIFFRACTION	1.5
5DA3	X-RAY DIFFRACTION	1.7
8S1C	X-RAY DIFFRACTION	1.75
6CZ3	X-RAY DIFFRACTION	1.8
5H2U	X-RAY DIFFRACTION	2.24
5D7V	X-RAY DIFFRACTION	2.33
6CZ2	X-RAY DIFFRACTION	2.5
1RJA	SOLUTION NMR
2KGT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13882-F1	88.79	0.61

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): 312 (proton acceptor)

Ligand- & substrate-binding residues (2): 197–205; 219

Post-translational modifications (7): 66, 114, 342, 351, 447, 13, 61

Mutagenesis-validated functional residues (9):

Position	Phenotype
44	strong decrease in stap2 phosphorylation. markedly decreased interaction between sh3 domain the linker region.
66	decrease in stap2 phosphorylation.
105	abolishes interaction with arap1.
105	decrease in stap2 phosphorylation.
184	abrogates interaction between ptk6-domain kinase and ptk6-linker. abrogates autophosphorylation and phosphorylation of k
219	abolishes kinase activity and cell transformation, and phosphorylation of stap2. reduces interaction with arap1.
219	abolishes kinase activity.
342	3-fold lower specific kinase activity. decreased, but still significant, autophosphorylation. decreased, but still signi
447	decrease in transforming potential and increase in the kinase activity level. decreased, but still significant, autophos

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21
R-HSA-69231	Cyclin D associated events in G1
R-HSA-8847993	ERBB2 Activates PTK6 Signaling
R-HSA-8849468	PTK6 Regulates Proteins Involved in RNA Processing
R-HSA-8849469	PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
R-HSA-8849470	PTK6 Regulates Cell Cycle
R-HSA-8849471	PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases
R-HSA-8849472	PTK6 Down-Regulation
R-HSA-8849473	PTK6 Expression
R-HSA-8849474	PTK6 Activates STAT3
R-HSA-8857538	PTK6 promotes HIF1A stabilization
R-HSA-9707564	Cytoprotection by HMOX1

MSigDB gene sets: 181 (showing top): GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_SCF_SKP2_MEDIATED_DEGRADATION_OF_P27_P21, BECKER_TAMOXIFEN_RESISTANCE_UP, GOBP_GROWTH, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_NEUROGENESIS, GOCC_RUFFLE

GO Biological Process (16): protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), tyrosine phosphorylation of STAT protein (GO:0007260), positive regulation of neuron projection development (GO:0010976), cell migration (GO:0016477), cell differentiation (GO:0030154), ERBB2 signaling pathway (GO:0038128), positive regulation of DNA replication (GO:0045740), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), positive regulation of cell cycle (GO:0045787), negative regulation of growth (GO:0045926), positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427), protein autophosphorylation (GO:0046777), intestinal epithelial cell differentiation (GO:0060575), negative regulation of protein tyrosine kinase activity (GO:0061099), cellular response to retinoic acid (GO:0071300)

GO Molecular Function (10): protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), signaling receptor binding (GO:0005102), ATP binding (GO:0005524), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (9): ruffle (GO:0001726), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear body (GO:0016604), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by PTK6	9
Cyclin E associated events during G1/S transition	1
Cyclin A:Cdk2-associated events at S phase entry	1
G1 Phase	1
Signaling by ERBB2	1
Cellular response to chemical stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cell surface receptor signaling pathway via JAK-STAT	2
protein tyrosine kinase activity	2
protein binding	2
phosphorylation	1
protein modification process	1
enzyme-linked receptor protein signaling pathway	1
peptidyl-tyrosine phosphorylation	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
cell motility	1
cellular developmental process	1
ERBB signaling pathway	1
DNA replication	1
regulation of DNA replication	1
positive regulation of DNA metabolic process	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
positive regulation of ERBB signaling pathway	1
cell cycle	1
positive regulation of cellular process	1
regulation of cell cycle	1
growth	1
regulation of growth	1
negative regulation of biological process	1
regulation of receptor signaling pathway via JAK-STAT	1
positive regulation of receptor signaling pathway via STAT	1
protein phosphorylation	1
columnar/cuboidal epithelial cell differentiation	1
digestive tract development	1
negative regulation of protein kinase activity	1
negative regulation of peptidyl-tyrosine phosphorylation	1
regulation of protein tyrosine kinase activity	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
protein kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

1950 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTK6	STAP2	Q9UGK3	958
PTK6	EGFR	P00533	948
PTK6	GPNMB	Q14956	944
PTK6	CHD8	Q9HCK8	782
PTK6	KHDRBS1	Q07666	737
PTK6	LRRK2	Q5S007	661
PTK6	SMARCA4	P51532	609
PTK6	KHDRBS2	Q5VWX1	591
PTK6	KHDRBS3	O75525	580
PTK6	EGF	P01133	578
PTK6	CHD9	Q3L8U1	510
PTK6	STAM	Q92783	505
PTK6	CTCF	P49711	500
PTK6	KRAS	P01116	487
PTK6	CHD6	Q8TD26	484

IntAct

138 interactions, top by confidence:

A	B	Type	Score
PTK6	EFHC2	psi-mi:“MI:0915”(physical association)	0.780
EFHC2	PTK6	psi-mi:“MI:0915”(physical association)	0.780
EXOC5	PTK6	psi-mi:“MI:0915”(physical association)	0.720
PTK6	EXOC5	psi-mi:“MI:0915”(physical association)	0.720
PTK6	PTK6	psi-mi:“MI:0217”(phosphorylation reaction)	0.710
PTK6	PTK6	psi-mi:“MI:0407”(direct interaction)	0.710
PTK6	PTK6	psi-mi:“MI:0914”(association)	0.710
FCHO1	PTK6	psi-mi:“MI:0915”(physical association)	0.670
PTK6	KHDRBS2	psi-mi:“MI:0915”(physical association)	0.670
KHDRBS2	PTK6	psi-mi:“MI:0915”(physical association)	0.670
PTK6	FCHO1	psi-mi:“MI:0915”(physical association)	0.670
PTK6	DDX17	psi-mi:“MI:0915”(physical association)	0.670
HTT	PTK6	psi-mi:“MI:0915”(physical association)	0.670
ERBB2	PTK6	psi-mi:“MI:0915”(physical association)	0.630
PTK6	ERBB2	psi-mi:“MI:0915”(physical association)	0.630
PTK6	SFPQ	psi-mi:“MI:0915”(physical association)	0.630
SFPQ	PTK6	psi-mi:“MI:0915”(physical association)	0.630

BioGRID (128): REL (Two-hybrid), WASL (Two-hybrid), EXOC5 (Two-hybrid), FCHO1 (Two-hybrid), CCDC33 (Two-hybrid), EFHC2 (Two-hybrid), KHDRBS2 (Two-hybrid), SOCS3 (Affinity Capture-Western), PTK6 (Affinity Capture-Western), CCT3 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT8 (Affinity Capture-MS), TCP1 (Affinity Capture-MS), PTK6 (Two-hybrid), PTK6 (Affinity Capture-RNA)

ESM2 similar proteins: F1RDG9, G5EE56, O13148, O45539, O73792, P00523, P00524, P00525, P00526, P00529, P00544, P04048, P05480, P06240, P09769, P10447, P11681, P12931, P13115, P14234, P16277, P17713, P25020, P27446, P29321, P31693, P32577, P41239, P41240, P41241, P42683, P42685, P42686, P42688, P42689, P42690, P51451, P63185, Q01621, Q05876

Diamond homologs: A0A0K3AV08, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, G5EE56, H2KZW3, O01700, O19064, O22558, O43283, O54967, O60674, P00529, P00533, P00534, P00535, P03949, P04412, P06239, P06240, P08069, P08922, P08941, P09760, P09769, P11273, P11362, P13388, P14234, P14616, P14617, P16092, P16591, P18461, P21802, P21803, P21804, P22607

SIGNOR signaling

36 interactions.

A	Effect	B	Mechanism
PTK6	up-regulates	AKT	phosphorylation
PTK6	up-regulates	STAT5B	phosphorylation
PTK6	“up-regulates activity”	BCAR1	phosphorylation
PTK6	up-regulates	BCAR1	phosphorylation
PTK6	up-regulates	ARHGAP5	phosphorylation
PTK6	“up-regulates activity”	STAP2	phosphorylation
PTK6	“up-regulates activity”	PTK6	phosphorylation
PTK6	unknown	KHDRBS1	phosphorylation
PTK6	up-regulates	AKT1	phosphorylation
PTK6	“up-regulates activity”	ARAP1	phosphorylation
PTK6	“up-regulates activity”	EPS8	phosphorylation
PTPN1	“down-regulates activity”	PTK6	dephosphorylation
PTK6	“down-regulates quantity”	CTNNB1	phosphorylation
PTK6	“down-regulates activity”	DOK1	phosphorylation
PTK6	“up-regulates activity”	STAT3	phosphorylation
PTK6	“up-regulates activity”	PTK2	phosphorylation
PTK6	“down-regulates activity”	CDC73	phosphorylation
PTK6	“up-regulates activity”	CNTNAP1	phosphorylation
PTK6	“down-regulates activity”	CBL	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by ERBB2 KD Mutants	5	55.6×	3e-06
Downregulation of ERBB2 signaling	5	50.1×	4e-06
Signaling by ERBB2	5	45.5×	6e-06
Negative regulation of the PI3K/AKT network	5	36.6×	1e-05
Constitutive Signaling by Aberrant PI3K in Cancer	8	26.7×	1e-07
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	9	22.9×	7e-08
PIP3 activates AKT signaling	9	15.8×	6e-07
RAF/MAP kinase cascade	7	11.2×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	8	42.2×	1e-08
positive regulation of miRNA transcription	5	30.9×	2e-04
phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	22.4×	5e-04
protein stabilization	7	10.0×	9e-04
positive regulation of ERK1 and ERK2 cascade	5	9.1×	1e-02
negative regulation of apoptotic process	10	7.4×	2e-04
positive regulation of gene expression	7	5.8×	1e-02
intracellular signal transduction	7	5.7×	1e-02

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — AML.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1787 predictions. Top by Δscore:

Variant	Effect	Δscore
20:63530188:CACT:C	acceptor_gain	1.0000
20:63530191:T:C	acceptor_gain	1.0000
20:63530742:CTA:C	donor_loss	1.0000
20:63530744:A:AT	donor_loss	1.0000
20:63530745:CCT:C	donor_loss	1.0000
20:63530923:AGAGT:A	acceptor_gain	1.0000
20:63530924:GAGT:G	acceptor_gain	1.0000
20:63530925:AGT:A	acceptor_gain	1.0000
20:63530926:GT:G	acceptor_gain	1.0000
20:63530926:GTCTG:G	acceptor_loss	1.0000
20:63530928:C:CC	acceptor_gain	1.0000
20:63530928:C:CG	acceptor_loss	1.0000
20:63530931:C:CT	acceptor_gain	1.0000
20:63532521:CTCA:C	donor_loss	1.0000
20:63532523:CACCG:C	donor_loss	1.0000
20:63532524:A:AC	donor_gain	1.0000
20:63532524:AC:A	donor_gain	1.0000
20:63532524:ACCG:A	donor_gain	1.0000
20:63532525:C:CG	donor_gain	1.0000
20:63532525:CC:C	donor_gain	1.0000
20:63532525:CCG:C	donor_gain	1.0000
20:63532525:CCGC:C	donor_gain	1.0000
20:63532525:CCGCG:C	donor_gain	1.0000
20:63532683:GTTGT:G	acceptor_gain	1.0000
20:63532684:TTGT:T	acceptor_gain	1.0000
20:63532685:TGT:T	acceptor_gain	1.0000
20:63532688:C:CC	acceptor_gain	1.0000
20:63534149:TACCT:T	donor_loss	1.0000
20:63534150:A:T	donor_loss	1.0000
20:63534151:C:CG	donor_loss	1.0000

AlphaMissense

2944 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:63533564:C:A	K219N	0.993
20:63533564:C:G	K219N	0.993
20:63530828:C:G	R311P	0.990
20:63530135:A:G	W371R	0.989
20:63530135:A:T	W371R	0.989
20:63530189:A:G	W353R	0.987
20:63530189:A:T	W353R	0.987
20:63534984:G:C	F102L	0.987
20:63534984:G:T	F102L	0.987
20:63534986:A:G	F102L	0.987
20:63530825:T:G	D312A	0.986
20:63529599:T:A	R431S	0.985
20:63529599:T:G	R431S	0.985
20:63530824:G:C	D312E	0.984
20:63530824:G:T	D312E	0.984
20:63530825:T:A	D312V	0.984
20:63533649:A:G	F191S	0.984
20:63530770:G:C	D330E	0.981
20:63530770:G:T	D330E	0.981
20:63530779:T:A	K327N	0.980
20:63530779:T:G	K327N	0.980
20:63530187:C:A	W353C	0.979
20:63530187:C:G	W353C	0.979
20:63529600:C:G	R431T	0.977
20:63530832:G:C	H310D	0.977
20:63530126:C:A	G374W	0.976
20:63530190:C:A	K352N	0.976
20:63530190:C:G	K352N	0.976
20:63530813:C:A	R316M	0.976
20:63530816:G:T	A315D	0.976

dbSNP variants (sampled 300 via entrez): RS1000042747 (20:63532921 T>A), RS1000096831 (20:63537526 G>A,T), RS1000142632 (20:63531825 C>A,G), RS1000689972 (20:63535667 G>A), RS1000956363 (20:63536336 G>A,C), RS1001391513 (20:63537036 G>A,T), RS1001652985 (20:63531757 A>T), RS1001712918 (20:63535624 G>A), RS1001738101 (20:63536856 AC>A,ACC), RS1001750461 (20:63535470 C>T), RS1002086160 (20:63534692 G>A,C,T), RS1002444564 (20:63530327 G>A,C), RS1003002281 (20:63535413 C>T), RS1003389122 (20:63534720 C>T), RS1003467336 (20:63539218 C>T)

Disease associations

OMIM: gene MIM:602004 | disease phenotypes: MIM:148300

GenCC curated gene-disease

Mondo (1): keratoconus (MONDO:0015486)

Orphanet (2): OBSOLETE: Keratoconus (Orphanet:156071), NON RARE IN EUROPE: Isolated keratoconus (Orphanet:2335)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000563	Keratoconus

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001942_22	Prostate cancer	4.000000e-16
GCST004521_202	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST005191_10	Hair shape	3.000000e-14
GCST008103_74	Bipolar disorder	8.000000e-07
GCST008115_28	Bipolar I disorder	3.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009963	bipolar I disorder

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007640	Keratoconus	C11.204.627

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4601 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

43 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 411,000 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL3936761	ZANUBRUTINIB	4	2,484
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL939	GEFITINIB	4	117,814
CHEMBL101253	VATALANIB	3	11,319
CHEMBL217092	SARACATINIB	3	3,982
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL3265032	ENTOSPLETINIB	3	1,628
CHEMBL3544983	TESEVATINIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL5095202	VIMSELTINIB	3
CHEMBL572881	MOTESANIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2
CHEMBL1738757	REBASTINIB	2
CHEMBL215152	DEFOSBARASERTIB	2
CHEMBL230011	TG100-115	2
CHEMBL2408045	SAPITINIB	2

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Src family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 19a [PMID: 21855335]	Inhibition	8.7	pIC50
tilfrinib	Inhibition	8.5	pIC50

Binding affinities (BindingDB)

17 measured of 30 human assays (30 total across all organisms); most potent 17 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
IBRUTINIB	IC50	0.8 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
N-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]prop-2-enamide	IC50	1.1 nM	US-9278100: Inhibitors of bruton’s tyrosine kinase for the treatment of solid tumors
Staurosporine	KD	1.7 nM
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole	KD	9.8 nM
N-[3-[2-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	IC50	10 nM	US-10266537: 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM
BMS-354825	KD	27 nM
4-(4-fluorophenyl)-3-pyridin-4-yl-1-(2,4,6-trichlorophenyl)pyrazol-5-amine	IC50	33 nM	US-9416123: Kinase modulators for the treatment of cancer
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
AMG 706	KD	300 nM
3-[4-(benzylamino)-3-methoxyphenyl]-1-[2-[4-(dimethylamino)piperidin-1-yl]ethyl]pyrazolo[3,4-d]pyrimidin-4-amine	IC50	550 nM	US-10294227: Compounds
CI-1033	KD	1700 nM
GEFITINIB	IC50	2300 nM	US-9416123: Kinase modulators for the treatment of cancer
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
N-[3-({5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide	IC50	3400 nM
1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine	KD	4500 nM
(4-chlorophenyl)-[4-(4-pyridylmethyl)phthalazin-1-yl]amine	KD	8800 nM

ChEMBL bioactivities

397 potent at pChembl≥5 of 412 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	Kd	2	nM	CHEMBL249097
8.70	Kd	2	nM	CHEMBL450519
8.70	IC50	2	nM	CHEMBL5874804
8.70	IC50	2	nM	CHEMBL5800577
8.70	IC50	2	nM	CHEMBL1836842
8.68	IC50	2.1	nM	CHEMBL5872498
8.60	IC50	2.5	nM	CHEMBL5280844
8.52	IC50	3	nM	CHEMBL6015269
8.52	IC50	3	nM	CHEMBL5975049
8.52	IC50	3	nM	CHEMBL5870629
8.52	IC50	3	nM	CHEMBL1836806
8.52	IC50	3	nM	CHEMBL1836844
8.52	IC50	3	nM	CHEMBL1836854
8.52	IC50	3	nM	CHEMBL1836863
8.50	IC50	3.15	nM	CHEMBL3133821
8.50	Ki	3.162	nM	CHEMBL1997617
8.49	IC50	3.2	nM	CHEMBL3133821
8.48	IC50	3.3	nM	IBRUTINIB
8.48	IC50	3.3	nM	CHEMBL3647967
8.48	IC50	3.3	nM	CHEMBL5862653
8.47	IC50	3.4	nM	CHEMBL6001291
8.43	IC50	3.7	nM	CHEMBL5759466
8.39	IC50	4.1	nM	CHEMBL3133815
8.39	IC50	4.1	nM	BRIGATINIB
8.39	IC50	4.1	nM	CHEMBL5760932
8.37	Kd	4.3	nM	FORETINIB
8.36	IC50	4.41	nM	CHEMBL3238103
8.33	IC50	4.7	nM	CHEMBL3133822
8.32	IC50	4.8	nM	CHEMBL3133828
8.32	IC50	4.75	nM	CHEMBL3133822
8.30	IC50	5	nM	CHEMBL6009199
8.30	IC50	5	nM	CHEMBL5843422
8.30	IC50	5	nM	CHEMBL5768073
8.30	IC50	5	nM	CHEMBL1836846
8.30	IC50	5	nM	CHEMBL1836842
8.30	Ki	5.012	nM	DASATINIB
8.29	IC50	5.1	nM	CHEMBL5834733
8.29	IC50	5.1	nM	CHEMBL5992742
8.28	IC50	5.3	nM	DASATINIB
8.27	IC50	5.4	nM	CHEMBL5983252
8.25	IC50	5.65	nM	CHEMBL3238097
8.24	IC50	5.7	nM	CHEMBL3133825
8.22	IC50	6	nM	CHEMBL6043320
8.22	IC50	6	nM	CHEMBL6007578
8.22	IC50	6	nM	CHEMBL1836755
8.22	IC50	6	nM	CHEMBL1836865
8.16	IC50	6.9	nM	CHEMBL5960550
8.15	IC50	7	nM	CHEMBL5811463
8.15	IC50	7	nM	CHEMBL5756049
8.15	IC50	7	nM	CHEMBL5793227

PubChem BioAssay actives

257 with measured affinity, of 1382 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
3-(4-amino-7-piperidin-4-ylpyrrolo[2,3-d]pyrimidin-5-yl)phenol	389068: Binding affinity to human BRK	kd	0.0020	uM
3-[[4-(5-hydroxy-2-methylanilino)pyrimidin-2-yl]amino]benzamide	389068: Binding affinity to human BRK	kd	0.0020	uM
[2-chloro-4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(2,2-dimethylpiperazin-1-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0020	uM
(2-chloro-4-phenoxyphenyl)-[4-[[(6S)-6-(hydroxymethyl)oxan-3-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone	1939137: Inhibition of BRK (unknown origin)	ic50	0.0025	uM
[4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]-3-fluorophenyl]-piperazin-1-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0030	uM
[4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]-3-fluorophenyl]-(2,2-dimethylpiperazin-1-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0030	uM
[2-chloro-4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(3,3-dimethylpiperazin-1-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0030	uM
4-[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-2-one	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0030	uM
3-(9H-pyrido[2,3-b]indol-4-ylamino)phenol	1125457: Inhibition of Brk (unknown origin) using [gamma-33P]-ATP after 60 mins by scintillation counting	ic50	0.0032	uM
Brigatinib	2182798: Inhibition of human PTK6 using poly (Glu, Tyr)4:1 as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.0041	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625029: Binding constant for BRK kinase domain	kd	0.0043	uM
N-(4-bromo-3-methoxyphenyl)-9H-pyrido[2,3-b]indol-4-amine	1125457: Inhibition of Brk (unknown origin) using [gamma-33P]-ATP after 60 mins by scintillation counting	ic50	0.0044	uM
N-(3-chlorophenyl)-9H-pyrido[2,3-b]indol-4-amine	1125457: Inhibition of Brk (unknown origin) using [gamma-33P]-ATP after 60 mins by scintillation counting	ic50	0.0047	uM
[2-chloro-4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-[(1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl]methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0050	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	1612819: Inhibition of BRK (unknown origin) preincubated for 10 mins followed by substrate addition and measured after 1 hr by ADP-Glo luminescence assay	ic50	0.0053	uM
N-(3-nitrophenyl)-9H-pyrido[2,3-b]indol-4-amine	1125457: Inhibition of Brk (unknown origin) using [gamma-33P]-ATP after 60 mins by scintillation counting	ic50	0.0056	uM
[4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]-3-fluorophenyl]-(3,3-dimethylpiperazin-1-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0060	uM
[2-chloro-4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0060	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0070	uM
[4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]-2-(trifluoromethyl)phenyl]-piperazin-1-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0070	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-[(1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl]methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0070	uM
2-amino-5-[2-[(3R)-3-aminopyrrolidin-1-yl]-6-fluoro-4-pyridinyl]-3-(3-hydroxy-2,6-dimethylphenyl)benzamide	2122452: Inhibition of BRK (unknown origin)	ic50	0.0080	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(4-methylpiperazin-1-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0080	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-morpholin-4-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0080	uM
(2,2-dimethylpiperazin-1-yl)-[3-fluoro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0090	uM
[3-fluoro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0100	uM
[3-ethoxy-5-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]thiophen-2-yl]-(3-methylpiperidin-1-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0100	uM
[2-chloro-4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(4,7-diazaspiro[2.5]octan-4-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0100	uM
(3,3-dimethylpiperazin-1-yl)-[3-fluoro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0100	uM
[2-chloro-4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0100	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(2,2-dimethylpiperazin-1-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0100	uM
1-[[5-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]thiophen-3-yl]methyl]piperidin-4-ol	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0100	uM
[2-chloro-4-[[6-ethyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0100	uM
5-bromo-4-N-(5-dimethylphosphoryl-2,3-dihydro-1,4-benzodioxin-6-yl)-2-N-[2-methoxy-4-[4-[3-(methoxymethyl)azetidin-1-yl]piperidin-1-yl]-5-methylphenyl]pyrimidine-2,4-diamine	1862885: Inhibition of BRK (unknown origin)	ic50	0.0110	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0110	uM
6-methyl-N-(2-piperazin-1-yl-4-pyridinyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0110	uM
N,N-dimethyl-5-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]-1,2-thiazole-3-carboxamide	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0120	uM
N-[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-3-(piperidin-1-ylmethyl)-1,2-thiazol-5-amine	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0130	uM
[2-chloro-4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(4,7-diazaspiro[2.5]octan-7-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0130	uM
[4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0150	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(4,7-diazaspiro[2.5]octan-4-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0160	uM
1-[4-[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]benzoyl]piperazin-1-yl]ethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0160	uM
Ibrutinib	1615369: Inhibition of human BRK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	ic50	0.0180	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(3,3-dimethylpiperazin-1-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0180	uM
[2-chloro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-(4,7-diazaspiro[2.5]octan-7-yl)methanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0190	uM
[2-methoxy-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-ylmethanone	621335: Inhibition of phosphorylation of SAM68 in 293 WT-PTK6 cells after 3 hrs	ic50	0.0220	uM
4-[3-[(6R,8aS)-1,1-dimethyl-3-oxo-6,7,8,8a-tetrahydro-5H-[1,3]oxazolo[3,4-a]pyridin-6-yl]-8-aminoimidazo[1,5-a]pyrazin-1-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]benzamide	1721756: Inhibition of PTK6 (unknown origin)	ic50	0.0240	uM
6-amino-7-(4-phenoxyphenyl)-9-[(3S)-1-prop-2-enoylpiperidin-3-yl]purin-8-one	1425144: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0250	uM
[4-[[6-cyclopropyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]-3-fluorophenyl]-morpholin-4-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0300	uM
[2-fluoro-4-[[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino]phenyl]-piperazin-1-ylmethanone	621334: Inhibition of BRK pretreated for 30 mins by microplate reader	ic50	0.0320	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects splicing, decreases expression, increases expression	2
sotorasib	affects cotreatment, decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
beta-lapachone	increases expression	1
arsenite	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	decreases expression	1
aflatoxin B2	increases methylation	1
abrine	increases expression	1
jinfukang	increases expression	1
ponatinib	decreases activity	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases response to substance	1
Fulvestrant	affects cotreatment, increases methylation	1
Eucalyptol	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Folic Acid	affects expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Vanadium	decreases expression	1
Paclitaxel	increases expression	1
Antirheumatic Agents	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	increases abundance, increases expression	1
Coal Ash	decreases expression	1

ChEMBL screening assays

332 unique, capped per target: 328 binding, 2 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1035880	Binding	Binding affinity to human BRK at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — J Med Chem
CHEMBL1839618	Functional	Inhibition of phosphorylation of SAM68 in 293 WT-PTK6 cells after 3 hrs	Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors. — Bioorg Med Chem Lett
CHEMBL4414919	ADMET	Inhibition of human BRK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8ND	Abcam HCT 116 PTK6 KO	Cancer cell line	Male
CVCL_B9QN	Abcam A-549 PTK6 KO	Cancer cell line	Male

Clinical trials (associated diseases)

279 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01485211	PHASE4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	PHASE4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	PHASE4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	PHASE4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	PHASE4	COMPLETED	Corneal Crosslinking Treatment Study
NCT07474870	PHASE4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT00371202	PHASE3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00647699	PHASE3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00815256	PHASE3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00887900	PHASE3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01112072	PHASE3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT01152541	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Progressive Keratoconus and Ectasia Using Riboflavin/Dextran and Hypotonic Riboflavin
NCT01190306	PHASE3	TERMINATED	Safety Study of the VEGA UV-A System to Treat Keratoconus
NCT01344187	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01459679	PHASE3	TERMINATED	Safety & Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery
NCT01464268	PHASE3	UNKNOWN	Transepithelial Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia
NCT01604135	PHASE3	ACTIVE_NOT_RECRUITING	Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial
NCT01643226	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01672814	PHASE3	COMPLETED	Microwave Treatment and Corneal Collagen Crosslinking for Keratoconus
NCT01682993	PHASE3	TERMINATED	Corneal Cross Linking and Topography Guided Excimer Laser Treatment
NCT01972854	PHASE3	TERMINATED	Safety and Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT02613780	PHASE3	UNKNOWN	Refractive Treatment of Early Keratoconus
NCT02638376	PHASE3	UNKNOWN	Evaluating the Safety and Efficacy of the KXL System for Corneal Collagen Cross-Linking in Eyes Having Keratoconus
NCT03080077	PHASE3	UNKNOWN	Safety and Effectiveness of Corneal Crosslinking (CXL): Keratoconus and Post-Refractive Ectasia
NCT03187912	PHASE3	COMPLETED	Accelerated Corneal Cross-linking With Different Riboflavin Solutions
NCT03442751	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus
NCT03858036	PHASE3	UNKNOWN	Corneal Collagen Cross-Linking (CXL) Performed With Epi-ON Versus Epi-OFF in Eyes With Keratoconus and Other Corneal Ectatic Disorders
NCT04897503	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Riboflavin/Dextran or Riboflavin/Methylcellulose
NCT04905108	PHASE3	UNKNOWN	Transepithelial (Epi-on) Corneal Collagen Crosslinking to Treat Keratoconus and Corneal Ectasia
NCT05027295	PHASE3	UNKNOWN	Accelerated Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Pulse or Continuous UV-A Light
NCT06100939	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age With Keratoconus
NCT06100952	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age with Keratoconus
NCT06450470	PHASE3	RECRUITING	Use of a Freeze-dried Amniotic Membrane Post Crosslinking in Subjects With Progressive Keratoconus
NCT06601101	PHASE3	RECRUITING	Effects of Topical Insulin on Corneal Epithelium Healing After Corneal Crosslinking in Patients With Keratoconus
NCT07124910	PHASE3	RECRUITING	Comparison of Epi-ON Corneal Collagen Crosslinking Performed Using an 18-Minute UVA Exposure vs. a 24-Minute UVA Exposure on Eyes With Ectatic Corneal Diseases
NCT07135167	PHASE3	RECRUITING	Compassionate Use Study of Epi-ON Corneal Collagen Crosslinking Performed Using UVA Exposure on Eyes With Ectatic Corneal Diseases for Subjects With Down Syndrome
NCT00409955	PHASE2	COMPLETED	Lamellar Transplant With Lyophilized Corneas
NCT00925327	PHASE2	UNKNOWN	Safety and Effectiveness of the UV-X System for Corneal Collagen Cross-Linking for Compassionate Treatment in Pediatric Patients With Progressive Keratoconus
NCT01143389	PHASE2	COMPLETED	Corneal Crosslinking in Patients With Keratoconus and Post-Refractive Ectasia
NCT01181219	PHASE2	COMPLETED	Transepithelial Corneal Collagen Cross-linking (CXL) in Treatment of Keratoconus