GRK6

Summary

GRK6 (G protein-coupled receptor kinase 6, HGNC:4545) is a protein-coding gene on chromosome 5q35.3, encoding G protein-coupled receptor kinase 6 (P43250). Specifically phosphorylates the activated forms of G protein-coupled receptors.

This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated forms of G protein-coupled receptors thus initiating their deactivation. Several transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 2870 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 77 total — 1 pathogenic
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001004106

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4545
Approved symbol	GRK6
Name	G protein-coupled receptor kinase 6
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198055
Ensembl biotype	protein_coding
OMIM	600869
Entrez	2870

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 20 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000355472, ENST00000355958, ENST00000393576, ENST00000502598, ENST00000506296, ENST00000507633, ENST00000508705, ENST00000511244, ENST00000512684, ENST00000515666, ENST00000528793, ENST00000881049, ENST00000881050, ENST00000881051, ENST00000930612, ENST00000930613, ENST00000930614, ENST00000954399, ENST00000954400, ENST00000954401, ENST00000954402, ENST00000954403

RefSeq mRNA: 4 — MANE Select: NM_001004106 NM_001004105, NM_001004106, NM_001364164, NM_002082

CCDS: CCDS34303, CCDS43406

Canonical transcript exons

ENST00000355472 — 16 exons

Exon	Start	End
ENSE00000898138	177431995	177432107
ENSE00001515898	177441737	177442891
ENSE00002047192	177426676	177426897
ENSE00003460469	177434902	177434939
ENSE00003493399	177433147	177433239
ENSE00003501243	177435032	177435121
ENSE00003519150	177440919	177441053
ENSE00003544554	177432706	177432806
ENSE00003556283	177433347	177433410
ENSE00003580727	177433536	177433676
ENSE00003592703	177430872	177430967
ENSE00003641149	177440700	177440837
ENSE00003663255	177433914	177434104
ENSE00003676856	177436393	177436530
ENSE00003680259	177432233	177432310
ENSE00003688787	177436073	177436281

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 97.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.4343 / max 1264.3588, expressed in 1808 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60478	16.9597	1801
60479	7.7169	1580
60481	0.7577	112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.21	gold quality
blood	UBERON:0000178	96.74	gold quality
monocyte	CL:0000576	96.50	gold quality
leukocyte	CL:0000738	96.35	gold quality
mononuclear cell	CL:0000842	96.31	gold quality
bone marrow cell	CL:0002092	95.93	gold quality
lymph node	UBERON:0000029	94.45	gold quality
spleen	UBERON:0002106	93.99	gold quality
bone marrow	UBERON:0002371	93.83	gold quality
vermiform appendix	UBERON:0001154	92.04	gold quality
type B pancreatic cell	CL:0000169	91.88	silver quality
caecum	UBERON:0001153	91.78	gold quality
pancreatic ductal cell	CL:0002079	91.16	silver quality
male germ cell	CL:0000015	90.68	gold quality
sperm	CL:0000019	90.46	gold quality
thymus	UBERON:0002370	90.19	gold quality
diaphragm	UBERON:0001103	89.43	silver quality
olfactory bulb	UBERON:0002264	89.34	gold quality
cervix squamous epithelium	UBERON:0006922	89.15	gold quality
epithelial cell of pancreas	CL:0000083	88.82	silver quality
trabecular bone tissue	UBERON:0002483	88.71	gold quality
tonsil	UBERON:0002372	88.70	gold quality
mucosa of transverse colon	UBERON:0004991	88.61	gold quality
buccal mucosa cell	CL:0002336	88.49	gold quality
epithelium of nasopharynx	UBERON:0001951	88.36	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.35	gold quality
tongue squamous epithelium	UBERON:0006919	88.18	gold quality
hair follicle	UBERON:0002073	88.05	silver quality
cardia of stomach	UBERON:0001162	87.95	gold quality
upper lobe of left lung	UBERON:0008952	87.94	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.41
E-MTAB-6058	no	6.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

78 targeting GRK6, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4271	99.88	68.32	2244

Literature-anchored findings (GeneRIF, showing 29)

• potential role of endogenous GRK6 in the regulation of M(3) mACh receptor (PMID:11856737)
• GRK6 is potential marker for organ injury and survival after cardiopulmonary bypass (PMID:12552191)
• the CRH-R1alpha carboxyl tail is important for regulation of receptor activity by G protein-coupled receptor kinase (PMID:15498832)
• the crystalline GRK6 RGS homology domain forms an extensive dimer interface using conserved hydrophobic residues distinct from those in GRK2 that bind Galpha(q) (PMID:16613860)
• These results suggest that the C-terminus of GRK6A contains a novel electrostatic palmitoyl switch in which acidic residues weaken the membrane-binding strength of the amphipathic helix.[GRK6A] (PMID:17538017)
• oxytocin receptor responsiveness is regulated by G protein-coupled receptor kinase 6 in human myometrial smooth muscle (PMID:19423652)
• Results identify GRK5/6 as novel kinases for the single transmembrane receptor LRP6 during Wnt signaling. (PMID:19801552)
• Recruitment of beta-Arrestin 2, but not beta-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor and Grk6 fails to associate with the WHIM-mutant receptor. (PMID:19956569)
• inhibition of GRK6 represents a uniquely targeted novel therapeutic strategy in human multiple myeloma. (PMID:19996089)
• A number of double mutations of GRK6 kinase within helices 3, 9, and 10 reduced phosphorylation of the beta2 adrenergic receptor and rhodopsin compared to wild-type GRK6 kinase. (PMID:20038610)
• A reduced cortical concentration of GRK6 in schizophrenia (resembling that in aging) may result in altered G protein-dependent signaling, thus contributing to prefrontal deficits in schizophrenia. (PMID:21784156)
• results suggested that GRK6 overexpression plays an important role in hepatocellular carcinoma (PMID:23375037)
• Downregulation of GRK6 expression enhances CXCR4 signaling and promoted medulloblastoma cell migration. (PMID:23497290)
• Our results imply that GRK6 may not play a role in the pathophysiology of schizophrenia among Han Chinese (PMID:24302161)
• GRK6 plays a predominant role in phosphorylation of FFA receptor (FFA)4. (PMID:24412271)
• these results indicate that GRK6 complexes with AGS3-Galphai2 to regulate CXCR2-mediated leukocyte functions at different levels, including downstream effector activation, receptor trafficking, and expression at the cell membrane. (PMID:24510965)
• The expression of GRK6 mRNA and protein was significantly lower in hypopharyngeal squamous cell carcinoma than in corresponding adjacent non-tumor tissues. This was associated with aberrant methylation of the gene. (PMID:26718636)
• demonstrate for the first time exosomal enrichment of G-protein-coupled receptor kinase (GRK) 5 and GRK6, both of which regulate Src and IGF-IR signaling and have been implicated in cancer. (PMID:27232975)
• Decreased expression of GRK6 may serve as an independent predictor of overall survival in lung adenocarcinoma. (PMID:27601164)
• This work demonstrates the importance of GRK6 in regulation of hematopoietic stem cell self-renewal and reveals its potential role in participation of stress response. (PMID:27882944)
• Genetic variation in OXTR and GRK6 is associated with the amount of oxytocin required as well as the duration of labor and risk for cesarean delivery among women undergoing induction of labor near term. (PMID:28526450)
• GRK6 overexpression can significantly enhance tumor proliferation and invasion, which was consistent with clinical findings. (PMID:29805156)
• Hypermethylation of the GRK6 gene promoter suppressed binding of C/EBPalpha, thereby contributing to the promotion of cell migration and invasion. (PMID:30984536)
• MiR-19b-3p attenuates IL-1beta induced extracellular matrix degradation and inflammatory injury in chondrocytes by targeting GRK6. (PMID:31227976)
• GRK6 S-nitrosylation at cys 474 enhances its kinase activity toward alpha-syn phosphorylation at S129. (PMID:32343709)
• Characterization of the G protein-coupled receptor kinase 6 promoter reveals a functional CREB binding site. (PMID:33600497)
• Multisite NHERF1 phosphorylation controls GRK6A regulation of hormone-sensitive phosphate transport. (PMID:33639163)
• M2 macrophages-derived exosomal miR-3917 promotes the progression of lung cancer via targeting GRK6. (PMID:36261031)
• The Role of G Protein-Coupled Receptor Kinase 6 Regulation in Inflammation and Pain. (PMID:36555521)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	grk6	ENSDARG00000032157
mus_musculus	Grk6	ENSMUSG00000074886
rattus_norvegicus	Grk6	ENSRNOG00000014615
drosophila_melanogaster	Gprk2	FBGN0261988
caenorhabditis_elegans		WBGENE00001708

Paralogs (7): GRK3 (ENSG00000100077), GRK7 (ENSG00000114124), GRK4 (ENSG00000125388), RSKR (ENSG00000167524), GRK2 (ENSG00000173020), GRK1 (ENSG00000185974), GRK5 (ENSG00000198873)

Protein

Protein identifiers

G protein-coupled receptor kinase 6 — P43250 (reviewed: P43250)

Alternative names: G protein-coupled receptor kinase GRK6

All UniProt accessions (8): D6R9V4, D6RC88, D6RDA3, D6RHC7, D6RHX8, F8W9W2, H0Y967, P43250

UniProt curated annotations — full annotation on UniProt →

Function. Specifically phosphorylates the activated forms of G protein-coupled receptors. Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their desensitization. Seems to be involved in the desensitization of D2-like dopamine receptors in striatum and chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor: LRP6 during Wnt signaling (in vitro).

Subunit / interactions. Interacts with GIT1.

Subcellular location. Membrane.

Tissue specificity. Widely expressed.

Post-translational modifications. It is uncertain whether palmitoylation is on Cys-561 and/or Cys-562 and/or Cys-565.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P43250-1	GRK6A	yes
P43250-2	GRK6B
P43250-3	GRK6C

RefSeq proteins (4): NP_001004105, NP_001004106, NP_001351093, NP_002073 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000239	GPCR_kinase	Family
IPR000719	Prot_kinase_dom	Domain
IPR000961	AGC-kinase_C	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016137	RGS	Domain
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR036305	RGS_sf	Homologous_superfamily
IPR044926	RGS_subdomain_2	Homologous_superfamily

Pfam: PF00069, PF00615

Enzyme classification (BRENDA):

• EC 2.7.11.16 — G-protein-coupled receptor kinase (BRENDA: 5 organisms, 89 substrates, 34 inhibitors, 5 Km, 0 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	0.014–0.02	3
RHODOPSIN	0.0012–0.0018	2

Catalyzed reactions (Rhea), 1 shown:

• [G-protein-coupled receptor] + ATP = [G-protein-coupled receptor]-phosphate + ADP + H(+) (RHEA:12008)

UniProt features (84 total): helix 32, strand 17, mutagenesis site 7, modified residue 4, binding site 4, domain 3, lipid moiety-binding region 3, splice variant 3, sequence variant 3, turn 3, sequence conflict 2, chain 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2ACX	X-RAY DIFFRACTION	2.6
3NYN	X-RAY DIFFRACTION	2.72
3NYO	X-RAY DIFFRACTION	2.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43250-F1	90.22	0.78

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): 311 (proton acceptor)

Ligand- & substrate-binding residues (4): 192–200; 215; 264–270; 315–318

Post-translational modifications (7): 484, 485, 566, 568, 561, 562, 565

Mutagenesis-validated functional residues (7):

Position	Phenotype
6	12-13 fold defects in kinase activity; 180-fold defects in kinase activity; when associated with a-7.
7	12-13 fold defects in kinase activity; 180-fold defects in kinase activity; when associated with a-6.
9	140-fold defects in kinase activity.
12	1100-fold defects in kinase activity.
561	abolishes palmitoylation; when associated with s-562 and s-565.
562	abolishes palmitoylation; when associated with s-561 and s-565.
565	abolishes palmitoylation; when associated with s-561 and s-562.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 279 (showing top): WWTAAGGC_UNKNOWN, GCANCTGNY_MYOD_Q6, MODULE_522, AREB6_01, GGGTGGRR_PAX4_03, USF_C, SRF_Q5_01, PID_CXCR4_PATHWAY, SRF_C, BLALOCK_ALZHEIMERS_DISEASE_UP, TCF11_01, E4F1_Q6, ACATTCC_MIR1_MIR206, LIAO_METASTASIS, AACTTT_UNKNOWN

GO Biological Process (6): G protein-coupled receptor signaling pathway (GO:0007186), regulation of G protein-coupled receptor signaling pathway (GO:0008277), regulation of signal transduction (GO:0009966), Wnt signaling pathway (GO:0016055), protein phosphorylation (GO:0006468), signal transduction (GO:0007165)

GO Molecular Function (9): G protein-coupled receptor kinase activity (GO:0004703), ATP binding (GO:0005524), beta-adrenergic receptor kinase activity (GO:0047696), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
protein kinase activity	2
cellular anatomical structure	2
G protein-coupled receptor activity	1
G protein-coupled receptor signaling pathway	1
regulation of signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
cell surface receptor signaling pathway	1
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate 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
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRK6	GIT1	Q9Y2X7	998
GRK6	GIT2	Q14161	943
GRK6	ARHGEF6	Q15052	774
GRK6	ARRB1	P49407	755
GRK6	ARRB2	P32121	735
GRK6	SAG	P10523	673
GRK6	ADRB2	P07550	664
GRK6	CXCR2	P25025	658
GRK6	PXN	P49023	637
GRK6	LTB4R	Q15722	532
GRK6	RHO	P08100	528
GRK6	CXCR4	P30991	520
GRK6	RASA1	P20936	489
GRK6	CXCR1	P25024	487
GRK6	OPRM1	P35372	474

IntAct

162 interactions, top by confidence:

A	B	Type	Score
APP	GRK6	psi-mi:“MI:0915”(physical association)	0.560
GRK4	GRK6	psi-mi:“MI:0915”(physical association)	0.560
HSP90AB1	GRK6	psi-mi:“MI:0915”(physical association)	0.560
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
GPR183	NRP1	psi-mi:“MI:0914”(association)	0.530
SPMIP4	PGK2	psi-mi:“MI:0914”(association)	0.530
HDGFL2	CDC7	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
GRK6	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
SHANK1	GRK6	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
NHERF4	GRK6	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
MAST1	GRK6	psi-mi:“MI:0407”(direct interaction)	0.440
PDZD7	GRK6	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	PARD3	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	GRK6	psi-mi:“MI:0407”(direct interaction)	0.440
GRK6	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (165): GRK6 (Affinity Capture-RNA), GRK6 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), GRK5 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), NOLC1 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), ENDOG (Affinity Capture-MS), GRK6 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), GRK6 (Affinity Capture-MS), GRK6 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I5ZNK2, B1H3E1, D3ZSZ3, D4ABL6, D4AE59, E1BMN8, E2QWQ2, E9PV86, O54804, O54949, O70293, P15209, P24786, P33497, P43250, P43291, P43292, P46892, P49137, P49138, P85298, P97711, Q03351, Q0GGW5, Q15831, Q16644, Q3SYZ2, Q3UMW7, Q5N942, Q5XIS9, Q63604, Q66H84, Q6ZI44, Q75H77, Q75V57, Q7XKA8, Q7XQP4, Q7Y0B9, Q8BZ03, Q8CIW5

Diamond homologs: A1A4I4, A1Z7T0, A7MBL8, B6CZ17, B6CZ18, J9W0G9, O08874, O19111, O70291, O70293, O97627, P04409, P05130, P05696, P09215, P09217, P10102, P10830, P12688, P13678, P16054, P17252, P18961, P21146, P23298, P24723, P25098, P26817, P26818, P26819, P28327, P28867, P31748, P31749, P31750, P31751, P32298, P32865, P32866, P34102

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
GRK6	“down-regulates activity”	BDKRB2	phosphorylation
GRK6	“down-regulates activity”	SLC9A3R1	phosphorylation
GRK6	“down-regulates activity”	MC1R	phosphorylation
GRK6	“down-regulates quantity by destabilization”	CXCR4	ubiquitination
GRK6	“down-regulates activity”	DRD2	phosphorylation
GRK6	“up-regulates activity”	LRP6	phosphorylation
GRK6	“down-regulates quantity”	CXCR2	phosphorylation
GRK6	unknown	GRK6	phosphorylation
GRK6	“down-regulates activity”	LTB4R	phosphorylation
GRK6	“down-regulates quantity by destabilization”	IGF1R	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 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
Ras activation upon Ca2+ influx through NMDA receptor	7	48.7×	9e-09
Unblocking of NMDA receptors, glutamate binding and activation	5	33.2×	3e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	33.2×	3e-05
Assembly and cell surface presentation of NMDA receptors	10	30.9×	1e-10
Dopamine Neurotransmitter Release Cycle	5	30.3×	4e-05
Long-term potentiation	5	29.0×	4e-05
Neurexins and neuroligins	11	26.4×	1e-10
Protein-protein interactions at synapses	7	22.7×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	52.0×	6e-14
protein localization to synapse	6	37.4×	3e-06
receptor clustering	7	35.5×	4e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	6	24.2×	2e-05
protein-containing complex assembly	10	9.3×	2e-05
cell-cell adhesion	11	9.1×	7e-06
protein localization to plasma membrane	7	6.2×	7e-03
chemical synaptic transmission	8	5.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	56
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
979536	GRCh37/hg19 5q35.2-35.3(chr5:175570677-177114151)x3	Pathogenic

SpliceAI

4150 predictions. Top by Δscore:

Variant	Effect	Δscore
5:177403252:AC:A	donor_gain	1.0000
5:177403253:CC:C	donor_gain	1.0000
5:177403477:GCA:G	donor_loss	1.0000
5:177403478:CA:C	donor_loss	1.0000
5:177403479:AC:A	donor_gain	1.0000
5:177403479:ACCCA:A	donor_loss	1.0000
5:177403480:C:T	donor_loss	1.0000
5:177403480:CC:C	donor_gain	1.0000
5:177403497:G:C	donor_gain	1.0000
5:177403613:CGGGC:C	acceptor_gain	1.0000
5:177403616:GCCT:G	acceptor_loss	1.0000
5:177403618:C:CC	acceptor_gain	1.0000
5:177403619:T:G	acceptor_loss	1.0000
5:177403715:T:TA	donor_gain	1.0000
5:177404189:T:TA	donor_gain	1.0000
5:177404352:C:CA	donor_gain	1.0000
5:177404915:C:CC	acceptor_gain	1.0000
5:177404916:T:C	acceptor_gain	1.0000
5:177404916:T:TC	acceptor_gain	1.0000
5:177405317:CCTCA:C	donor_loss	1.0000
5:177405318:CTCAC:C	donor_loss	1.0000
5:177405319:TCAC:T	donor_loss	1.0000
5:177405320:CACCT:C	donor_loss	1.0000
5:177405322:C:CG	donor_loss	1.0000
5:177405322:CCTTT:C	donor_gain	1.0000
5:177405430:TGGT:T	acceptor_gain	1.0000
5:177405434:C:CA	acceptor_loss	1.0000
5:177405434:C:CC	acceptor_gain	1.0000
5:177405441:A:AC	acceptor_gain	1.0000
5:177405441:A:C	acceptor_gain	1.0000

AlphaMissense

3775 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:177426853:T:A	L3H	1.000
5:177426872:C:A	N9K	1.000
5:177426872:C:G	N9K	1.000
5:177433223:T:A	W173R	1.000
5:177433223:T:C	W173R	1.000
5:177433370:T:C	F186S	1.000
5:177433373:G:C	R187T	1.000
5:177433373:G:T	R187M	1.000
5:177433374:G:C	R187S	1.000
5:177433374:G:T	R187S	1.000
5:177433378:T:G	Y189D	1.000
5:177433382:G:C	R190P	1.000
5:177433388:T:A	L192Q	1.000
5:177433390:G:A	G193S	1.000
5:177433390:G:C	G193R	1.000
5:177433390:G:T	G193C	1.000
5:177433391:G:A	G193D	1.000
5:177433391:G:T	G193V	1.000
5:177433394:A:T	K194I	1.000
5:177433395:A:C	K194N	1.000
5:177433395:A:T	K194N	1.000
5:177433396:G:A	G195S	1.000
5:177433396:G:C	G195R	1.000
5:177433396:G:T	G195C	1.000
5:177433397:G:A	G195D	1.000
5:177433397:G:C	G195A	1.000
5:177433397:G:T	G195V	1.000
5:177433399:G:C	G196R	1.000
5:177433400:G:A	G196D	1.000
5:177433402:T:A	F197I	1.000

dbSNP variants (sampled 300 via entrez): RS1000004477 (5:177426488 GGTGAC>G), RS1000268936 (5:177438403 G>A), RS1000375801 (5:177437511 A>G), RS1000635037 (5:177425267 A>C), RS1000688751 (5:177439771 T>C), RS1000746638 (5:177437750 G>A), RS1001057926 (5:177440095 G>C), RS1001116742 (5:177426960 C>G,T), RS1001139848 (5:177433836 G>A), RS1001173430 (5:177442222 C>T), RS1001266672 (5:177442438 C>T), RS1001279841 (5:177436818 A>G), RS1001402442 (5:177427324 G>A,T), RS1001501276 (5:177430569 A>C,G,T), RS1001574930 (5:177430337 C>A)

Disease associations

OMIM: gene MIM:600869 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000649_23	Chronic kidney disease	1.000000e-14
GCST001574_7	Activated partial thromboplastin time	6.000000e-88
GCST001639_21	Metabolite levels	3.000000e-14
GCST005316_645	Intelligence (MTAG)	3.000000e-11
GCST005956_15	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005957_13	Waist-to-hip ratio adjusted for BMI (age <50)	3.000000e-07
GCST005962_42	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-08
GCST007044_13	Extremely high intelligence	3.000000e-08
GCST007638_34	Glycine levels	7.000000e-14
GCST008309_12	Cardiac troponin-I levels	2.000000e-07
GCST011541_5	Tinnitus	2.000000e-07
GCST90002399_433	Neutrophil percentage of white cells	1.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0004337	intelligence
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009767	glycine measurement
EFO:0010071	cardiac troponin I measurement
EFO:0007990	neutrophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6144 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 89,545 (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
CHEMBL535	SUNITINIB	4	79,020
CHEMBL495727	AT-9283	2	1,376
CHEMBL8260	BAICALEIN	2	8,592
CHEMBL3544932	TAK-901	1	557

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — GRK4 subfamily

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
balanol	Inhibition	6.31	pIC50

Binding affinities (BindingDB)

36 measured of 49 human assays (51 total across all organisms); most potent 36 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
methyl 2-amino-1-prop-2-enylpyrrolo[3,2-b]quinoxaline-3-carboxylate	IC50	973 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
methyl 2-amino-1-pentylpyrrolo[3,2-b]quinoxaline-3-carboxylate	IC50	1030 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
(4S,12aR)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide	IC50	1370 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
methyl 2-amino-1-hexylpyrrolo[3,2-b]quinoxaline-3-carboxylate	IC50	1430 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
2-[[5-(3-methylphenyl)-1H-1,2,4-triazol-3-yl]sulfanyl]acetic acid	IC50	1440 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
2-amino-1-butylpyrrolo[3,2-b]quinoxaline-3-carbonitrile	IC50	1560 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
4-ethoxy-1,3-dimethyl-2H-cyclohepta[c]pyrrol-8-one	IC50	2550 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
ethyl 2-amino-1-cyclopropylpyrrolo[3,2-b]quinoxaline-3-carboxylate	IC50	2830 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
4-ethoxy-1,3-dimethyl-2-(4-methylphenyl)cyclohepta[c]pyrrol-8-one	IC50	3400 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
6-(3,4-dihydroxyphenyl)-4-ethoxy-1,3-dimethylcyclohepta[c]furan-8-one	IC50	4410 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
7-[(4-ethoxyanilino)-pyridin-2-ylmethyl]quinolin-8-ol	IC50	4480 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
2-[(5-thiophen-2-yl-1H-1,2,4-triazol-3-yl)sulfanyl]acetic acid	IC50	4600 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
2-[[5-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]sulfanyl]acetic acid	IC50	5920 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
7-[[(5-methyl-1,2-oxazol-3-yl)amino]-pyridin-2-ylmethyl]quinolin-8-ol	IC50	6450 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
2,7-diamino-4-(6-chloro-[1,3]dioxolo[4,5-g]quinolin-7-yl)-4H-chromene-3-carbonitrile	IC50	6480 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
5-(4-chloro-3-nitrophenyl)-N-(furan-2-ylmethyl)-3,6-dihydro-1,3,4-thiadiazin-2-imine	IC50	6620 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
4-[(3aS,4R,9bR)-8-iodo-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl]benzoic acid	IC50	6660 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
7-[pyridin-3-yl-(pyridin-2-ylamino)methyl]quinolin-8-ol	IC50	6750 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
(5Z)-5-[(3,4-dihydroxyphenyl)methylidene]-2-(2,3-dimethylphenyl)imino-1,3-thiazolidin-4-one	IC50	7110 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
7,8-dihydroxy-4-(4-methoxyphenyl)chromen-2-one	IC50	7160 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
5-(diethylamino)-2-(2,3-dihydro-1H-perimidin-2-yl)phenol	IC50	8440 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
4-[[4-(diethylamino)phenyl]-(3-hydroxy-5-methylpyrazolidin-4-yl)methyl]-5-methylpyrazolidin-3-ol	IC50	9930 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
3-methyl-8-(3-morpholin-4-ylpropyliminomethyl)-5-propan-2-yl-2-[1,6,7-trihydroxy-3-methyl-8-(3-morpholin-4-ylpropyliminomethyl)-5-propan-2-ylnaphthalen-2-yl]naphthalene-1,6,7-triol	IC50	10100 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
7-[(4-methoxyanilino)-pyridin-2-ylmethyl]quinolin-8-ol	IC50	10300 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
N-(furan-2-ylmethyl)-5-(4-phenylphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-imine	IC50	10400 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
2,7-diamino-4-thiophen-2-yl-4H-chromene-3-carbonitrile	IC50	11800 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
2-(hydroxymethyl)-5-(5-methyl-2-nitroanilino)oxolane-3,4-diol	IC50	12000 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
9bH-perimidine	IC50	12500 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
1,4-diamino-9,10-dioxoanthracene-2-carboxamide	IC50	12600 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
3-methyl-8-(3-morpholin-4-ylpropyliminomethyl)-5-propan-2-yl-2-[1,6,7-trihydroxy-3-methyl-8-(3-morpholin-4-ylpropyliminomethyl)-5-propan-2-ylnaphthalen-2-yl]naphthalene-1,6,7-triol	IC50	16900 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
2-[2-(4-aminophenyl)ethyl]-1,3-benzoxazol-5-amine	IC50	17800 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
5-[2-keto-2-(2,3,4-trihydroxyphenyl)ethyl]furan-2-carboxylic acid ethyl ester	IC50	19400 nM
2,7-diamino-4-(4-methylphenyl)-4H-chromene-3-carbonitrile	IC50	26000 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
4-(11-azatetracyclo[8.7.0.02,7.013,17]heptadeca-1(10),2,4,6,8,11,13(17)-heptaen-12-yl)benzene-1,2-diol	IC50	28400 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
(5E)-5-[(4-hydroxy-3-methoxyphenyl)methylidene]-3-pyridin-3-yl-2-sulfanylidene-1,3-thiazolidin-4-one	IC50	40600 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides
12-amino-1-hydroxy-15-oxatetracyclo[7.6.1.02,7.013,16]hexadeca-2,4,6,9(16),10,12-hexaene-8,14-dione	IC50	47000 nM	US-10252984: Inhibiting G protein coupled receptor 6 kinase polypeptides

ChEMBL bioactivities

173 potent at pChembl≥5 of 230 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.46	IC50	3.5	nM	CHEMBL4852125
8.42	IC50	3.8	nM	CHEMBL4877302
8.22	IC50	6	nM	CHEMBL4860332
8.14	IC50	7.2	nM	CHEMBL4854871
8.10	IC50	8	nM	CHEMBL4877302
8.00	IC50	10	nM	CHEMBL4855000
7.96	IC50	11	nM	CHEMBL4875929
7.80	IC50	16	nM	CHEMBL4874424
7.75	IC50	18	nM	CHEMBL4847703
7.75	IC50	18	nM	CHEMBL4854871
7.70	IC50	20	nM	CHEMBL4876072
7.70	IC50	20	nM	CHEMBL6151486
7.66	IC50	22	nM	CHEMBL5569207
7.57	IC50	27	nM	CHEMBL4871944
7.57	IC50	27	nM	CHEMBL4872426
7.54	IC50	29	nM	CHEMBL4870615
7.52	IC50	30	nM	CHEMBL4877302
7.50	IC50	32	nM	CHEMBL6146311
7.48	IC50	32.9	nM	STAUROSPORINE
7.48	IC50	33	nM	CHEMBL4847703
7.48	IC50	33	nM	CHEMBL6152550
7.47	IC50	34	nM	CHEMBL6159900
7.44	IC50	36	nM	CHEMBL6162554
7.40	IC50	40	nM	CHEMBL4846282
7.40	IC50	40	nM	CHEMBL6164395
7.40	IC50	40	nM	CHEMBL6162335
7.40	IC50	40	nM	CHEMBL6164393
7.39	IC50	41	nM	CHEMBL4847311
7.37	IC50	42.4	nM	STAUROSPORINE
7.30	IC50	50	nM	CHEMBL6161120
7.22	IC50	60	nM	CHEMBL6168617
7.22	IC50	60	nM	CHEMBL6151812
7.21	IC50	61.7	nM	STAUROSPORINE
7.21	IC50	62	nM	CHEMBL5574633
7.16	IC50	70	nM	CHEMBL4850937
7.04	IC50	91	nM	CHEMBL4849245
7.00	IC50	100	nM	CHEMBL4860927
7.00	IC50	100	nM	CHEMBL6161413
6.96	IC50	110	nM	CHEMBL4876138
6.96	IC50	110	nM	CHEMBL6152245
6.92	IC50	120	nM	CHEMBL4848826
6.89	IC50	130	nM	CHEMBL6145814
6.85	IC50	140	nM	CHEMBL4860406
6.80	IC50	160	nM	CHEMBL4860226
6.77	IC50	170	nM	CHEMBL4860332
6.75	IC50	180	nM	CHEMBL4848792
6.72	IC50	190	nM	CHEMBL4858397
6.72	IC50	190	nM	CHEMBL6162930
6.66	IC50	220	nM	CHEMBL6159848
6.64	IC50	230	nM	CHEMBL4875743

PubChem BioAssay actives

57 with measured affinity, of 656 total; 46 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
2-N-[(1S)-1-(5-chloro-2-pyridinyl)ethyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)-5-methoxyquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0035	uM
2-N-[(4-chloro-2-methoxyphenyl)methyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)-5-methoxyquinazoline-2,4-diamine	1751900: Inhibition of human GRK6 using casein as substrate in presence of [gamma33P]ATP by radiometric hotspot kinase assay	ic50	0.0038	uM
2-N-[(4-chloro-2-methoxyphenyl)methyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)-5-methylquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0060	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-5-methoxyquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0072	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-5-methoxy-2-N-(2-phenylethyl)quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0100	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-5-methylquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0110	uM
2-N-[(4-chlorophenyl)methyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)-5-methoxyquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0160	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(5-fluoro-2-pyridinyl)methyl]-5-methoxyquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0180	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-5-fluoro-2-N-(2-phenylethyl)quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0200	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-5-fluoro-2-N-[(1S)-1-(4-methylphenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0270	uM
2-N-[(4-chlorophenyl)methyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)-5-methylquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0270	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-5-fluoro-2-N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0290	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715329: Inhibition of human GRK6 using casein as substrate by [gamma-33P]-ATP assay	ic50	0.0329	uM
2-N-[(4-chloro-2-methoxyphenyl)methyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0400	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-5-fluoro-2-N-[(1S)-1-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0410	uM
2-N-[(1S)-1-(4-chlorophenyl)ethyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0700	uM
6-[(1S)-1-[[4-[(5-ethyl-1H-pyrazol-3-yl)amino]-5-fluoroquinazolin-2-yl]amino]ethyl]pyridine-3-carbonitrile	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.0910	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-7-fluoro-2-N-[(1S)-1-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.1000	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-5-fluoro-2-N-[2-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.1100	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.1200	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(4-fluorophenyl)ethyl]-6-methoxyquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.1400	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-6-fluoro-2-N-[(1S)-1-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.1600	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-7-fluoro-2-N-[2-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.1800	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[2-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.1900	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-5-fluoro-2-N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.2300	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(4-fluorophenyl)methyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.2500	uM
4-N-(1-ethylimidazol-4-yl)-5-fluoro-2-N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.2800	uM
2-N-[1-(4-chlorophenyl)cyclopropyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.2800	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(4-methoxyphenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.2900	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-6-fluoro-2-N-[2-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.3100	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(3-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.3400	uM
7-chloro-4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.4400	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[2-(4-fluorophenyl)ethyl]-6-methoxyquinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.4600	uM
2-[2,6-dihydroxy-4-[(3R,4R)-3-[(4-hydroxybenzoyl)amino]azepan-4-yl]oxycarbonylbenzoyl]-3-hydroxybenzoic acid	464312: Inhibition of GRK6-mediated bovine tubulin phosphorylation by scintillation counting	ic50	0.4900	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637080: Inhibition of full-length recombinant human GST-tagged GRK6 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.5000	uM
2-N-[(1S)-1-cyclohexylethyl]-4-N-(5-ethyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	0.9600	uM
7-chloro-4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[2-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	1.1000	uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide	1425012: 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	1.1890	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-5-fluoro-2-N-(2-morpholin-4-ylethyl)quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	1.4000	uM
4-N-(5-ethyl-1H-pyrazol-3-yl)-2-N-[(1R)-1-(4-fluorophenyl)ethyl]quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	1.4000	uM
Sunitinib	1425012: 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	1.6150	uM
N-[(1R,6R)-6-amino-2,2-difluorocyclohexyl]-4-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-5-methylthiophene-2-carboxamide	1637080: Inhibition of full-length recombinant human GST-tagged GRK6 expressed in baculovirus expression system by Z’-LYTE assay	ic50	1.7000	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148462: Binding affinity to human GRK6 incubated for 45 mins by Kinobead based pull down assay	kd	2.4258	uM
5-fluoro-2-N-(2-phenylethyl)-4-N-(1H-pyrazol-5-yl)quinazoline-2,4-diamine	1751877: Inhibition of recombinant full-length human GRK6 using casein as substrate measured after 80 mins in presence of [gamma33P]ATP by radiometric scintillation counting method	ic50	2.5000	uM
3-[(3-methoxyphenyl)methyl]-6-(1H-pyrazol-4-yl)quinazolin-4-one	1698798: Inhibition of human GRK6	ic50	3.2700	uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1336069: Inhibition of human recombinant full length GST-tagged GRK6 expressed in baculovirus expression system	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	3
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
entinostat	increases expression, affects cotreatment	2
Acrolein	increases oxidation, increases abundance, affects cotreatment	2
Air Pollutants	affects expression, affects cotreatment, increases abundance, increases oxidation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
TAK-243	increases sumoylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression, affects cotreatment, increases abundance	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
belinostat	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Carvedilol	affects cotreatment, decreases reaction, increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Coumestrol	increases expression	1
Doxorubicin	decreases expression	1
Lead	decreases expression	1

ChEMBL screening assays

137 unique, capped per target: 137 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1038408	Binding	Residual activity of GRK6 at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1MY	Abcam K-562 GRK6 KO	Cancer cell line	Female
CVCL_D2JI	Abcam Raji GRK6 KO	Cancer cell line	Male
CVCL_SQ57	HAP1 GRK6 (-) 1	Cancer cell line	Male
CVCL_SQ58	HAP1 GRK6 (-) 2	Cancer cell line	Male
CVCL_UQ65	Abcam Jurkat GRK6 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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