GAK

Summary

GAK (cyclin G associated kinase, HGNC:4113) is a protein-coding gene on chromosome 4p16.3, encoding Cyclin-G-associated kinase (O14976). Associates with cyclin G and CDK5. It is a selective cancer dependency (DepMap: 42.3% of cell lines).

In all eukaryotes, the cell cycle is governed by cyclin-dependent protein kinases (CDKs), whose activities are regulated by cyclins and CDK inhibitors in a diverse array of mechanisms that involve the control of phosphorylation and dephosphorylation of Ser, Thr or Tyr residues. Cyclins are molecules that possess a consensus domain called the ‘cyclin box.’ In mammalian cells, 9 cyclin species have been identified, and they are referred to as cyclins A through I. Cyclin G is a direct transcriptional target of the p53 tumor suppressor gene product and thus functions downstream of p53. GAK is an association partner of cyclin G and CDK5. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 2580 — RefSeq curated summary.

At a glance

• GWAS associations: 22
• Clinical variants (ClinVar): 295 total
• Druggable target: yes — 77 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 42.3% of screened cell lines
• MANE Select transcript: NM_005255

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4113
Approved symbol	GAK
Name	cyclin G associated kinase
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	DNAJC26
Ensembl gene	ENSG00000178950
Ensembl biotype	protein_coding
OMIM	602052
Entrez	2580

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 49 protein_coding, 8 retained_intron, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000314167, ENST00000502656, ENST00000502799, ENST00000504435, ENST00000504668, ENST00000504947, ENST00000505819, ENST00000507124, ENST00000507580, ENST00000507991, ENST00000509566, ENST00000510022, ENST00000510799, ENST00000511163, ENST00000511229, ENST00000511345, ENST00000511980, ENST00000511983, ENST00000512325, ENST00000513935, ENST00000515868, ENST00000628912, ENST00000904261, ENST00000904262, ENST00000904263, ENST00000904264, ENST00000904265, ENST00000904266, ENST00000904267, ENST00000904268, ENST00000904269, ENST00000904270, ENST00000904271, ENST00000904272, ENST00000904273, ENST00000904274, ENST00000904275, ENST00000904276, ENST00000904277, ENST00000904278, ENST00000904279, ENST00000904280, ENST00000904281, ENST00000904282, ENST00000904283, ENST00000904284, ENST00000904285, ENST00000935920, ENST00000935922, ENST00000935923, ENST00000935924, ENST00000935925, ENST00000935926, ENST00000935927, ENST00000935928, ENST00000935929, ENST00000935930, ENST00000935931, ENST00000935932, ENST00000935933, ENST00000958843, ENST00000958844, ENST00000958845, ENST00000958846

RefSeq mRNA: 2 — MANE Select: NM_005255 NM_001318134, NM_005255

CCDS: CCDS3340, CCDS82902

Canonical transcript exons

ENST00000314167 — 28 exons

Exon	Start	End
ENSE00001676070	881907	882040
ENSE00001724136	877615	877809
ENSE00001733142	888847	888970
ENSE00001766171	882697	882819
ENSE00001767657	877090	877207
ENSE00001800201	884037	884086
ENSE00001801846	876530	876609
ENSE00001953279	932043	932316
ENSE00003459487	868539	868685
ENSE00003471083	883315	883463
ENSE00003488504	904637	904779
ENSE00003503042	893874	894009
ENSE00003505076	866956	867432
ENSE00003512443	865122	865244
ENSE00003518315	893377	893489
ENSE00003523192	851750	851974
ENSE00003530334	870711	870904
ENSE00003544808	912735	912794
ENSE00003548660	898033	898158
ENSE00003549146	850936	851084
ENSE00003552719	890532	890622
ENSE00003568841	859606	859722
ENSE00003594343	911673	911787
ENSE00003613120	896460	896549
ENSE00003649530	913607	913668
ENSE00003656355	866364	866534
ENSE00003668613	849892	850068
ENSE00003841858	849277	849774

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.6758 / max 2677.4658, expressed in 1824 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51030	34.8153	1821
51029	5.4247	1639
51031	1.3033	872
51026	0.0514	17
51027	0.0303	7
51028	0.0187	4
51021	0.0177	3
51022	0.0144	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	99.55	gold quality
endothelial cell	CL:0000115	98.66	gold quality
mucosa of transverse colon	UBERON:0004991	98.29	gold quality
cervix squamous epithelium	UBERON:0006922	98.12	gold quality
lower esophagus mucosa	UBERON:0035834	97.72	gold quality
granulocyte	CL:0000094	97.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.99	gold quality
minor salivary gland	UBERON:0001830	96.94	gold quality
transverse colon	UBERON:0001157	96.87	gold quality
metanephros cortex	UBERON:0010533	96.87	gold quality
ileal mucosa	UBERON:0000331	96.73	gold quality
cerebellar hemisphere	UBERON:0002245	96.70	gold quality
left testis	UBERON:0004533	96.70	gold quality
body of stomach	UBERON:0001161	96.67	gold quality
right testis	UBERON:0004534	96.64	gold quality
cerebellar cortex	UBERON:0002129	96.62	gold quality
spleen	UBERON:0002106	96.60	gold quality
saliva-secreting gland	UBERON:0001044	96.44	gold quality
small intestine	UBERON:0002108	96.44	gold quality
mucosa of stomach	UBERON:0001199	96.41	gold quality
mouth mucosa	UBERON:0003729	96.32	gold quality
body of uterus	UBERON:0009853	96.21	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.20	gold quality
right uterine tube	UBERON:0001302	96.15	gold quality
pylorus	UBERON:0001166	96.01	gold quality
cerebellum	UBERON:0002037	95.90	gold quality
upper lobe of left lung	UBERON:0008952	95.89	gold quality
adenohypophysis	UBERON:0002196	95.75	gold quality
left uterine tube	UBERON:0001303	95.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.80
E-CURD-11	no	25.69

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting GAK, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-4746-3P	82.55	60.61	60

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 42.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 31)

• down-regulation of GAK results in outgrowth of cells in soft agar, raising the possibility that loss of GAK function may promote tumorigenesis. (PMID:15240878)
• GAK enhanced the androgen receptor transcriptional response even at low concentrations of androgens (PMID:16161052)
• Results describe the recruitment dynamics of GAK and auxilin to clathrin-coated pits during endocytosis. (PMID:16895969)
• Interactions between the PsiG[PDE][PsiLM]-motif sequences in GAK and the AP1-gamma-ear domain are critical for the recruitment of GAK to the trans-Golgi network and the function of GAK in lysosomal enzyme sorting. (PMID:17538018)
• The GAK localizes in both cytoplasm and nucleus by immunostaining, ectopic expression of GFP-GAK and pull-down assays using dissected GAK fragments. (PMID:19371378)
• GAK and CHC cooperated in the same pathway and interacted in mitosis to regulate the formation of a functional spindle. (PMID:19654208)
• results identify a role for GAK and clathrin in microtubule outgrowth from kinetochores/chromosomes and suggest that GAK acts through clathrin to control microtubule outgrowth around chromosomes (PMID:20237935)
• Osteosarcoma cell proliferation and survival are dependent on GAK. (PMID:20881269)
• GAK is a new candidate for investigation in future studies. (PMID:21058943)
• cyclin G associated kinase is associated with Parkinson disease risk and suggest that cyclin G associated kinase and alpha-synuclein interact in a pathway involved in disease pathogenesis (PMID:21258085)
• study demonstrated that the rs1564282 variant in GAK (PARK17) increases the risk of Parkinson’s disease in Han Chinese patients from mainland China (PMID:22198721)
• GAK as a regulator of dephosphorylation events under the control of the PP2A B’gamma subunit. (PMID:22262175)
• Dominant negative mutants of IRAK4 and GAK show strong apoptotic effects in A498 cells under anoxia. (PMID:23591012)
• rs11248060 significantly increasThis study found that the minor alleles of GAK rpopulationss1564282 and DGKQ e the risk of PD in Han Chinese . (PMID:23618683)
• neither the CT, TT genotypes nor the minor allele T of single nucleotide polymorphism rs1564282 were associated with Parkinson’s disease among the subjects from Taiwan and Singapore. (PMID:23826309)
• The effects of rs11248051 and rs1564282 variants of GAK, and the rs3129882 variant of HLA-DRA, were investigated in Parkinson’s disease patients. (PMID:24039160)
• GAK apo structure reveals a dimeric inactive state of the catalytic domain mediated by an unusual activation segment interaction. (PMID:24438162)
• Cyclin-G-associated kinase is a binding partners of LRRK2, a candidate genes for risk for sporadic Parkinson disease, and part of a complex that promotes clearance of Golgi-derived vesicles through the autophagy-lysosome system. (PMID:24510904)
• AAK1 and GAK are critical regulators of HCV entry that function in part by activating EGFR, AP2M1, and NUMB, and as the molecular targets underlying the antiviral effect of sunitinib and erlotinib, respectively. (PMID:25653444)
• Data indicated that GBA and TMEM175/GAK significantly alter age at onset in PD. (PMID:25914293)
• This meta-analysis suggests that GAK rs1564282 C/T polymorphism is associated with increased susceptibility to Parkinson’s disease–{REVIEW} (PMID:25975492)
• We filtered four OSCC genes including SERPINB9, SERPINE2, GAK, and HSP90B1 through the gene global prioritization score (P < 0.005). (PMID:26318431)
• that the multiple single nucleotide polymorphisms of GAK synergistically participate in the pathogenesis of sporadic Parkinson’s disease through multiple pathways. (PMID:26676575)
• GAK gene expression is increased in Parkinson disease (PMID:27508417)
• These results suggest that the c-Src_GAK_MCM axis plays an important role in cell cycle progression through control of the DNA replication licensing system. (PMID:28135906)
• These findings indicate that the abnormal mitoses seen after silencing OIP5-AS1 were caused by an untimely rise in GAK levels and suggest that OIP5-AS1 suppresses cell proliferation at least in part by reducing GAK levels. (PMID:28472763)
• We have demonstrated that siRNA-mediated GAK silencing causes marked cell cycle disruption resulting in a raised sub-G1 alongside decreased G1 and G2/M cell cycle phases. Dual FBXW7-GAK inhibition increases multipolar mitoses (PMID:28829765)
• Dynamics of Auxilin 1 and GAK in clathrin-mediated traffic. (PMID:31962345)
• Mutation Analysis of DNAJC Family for Early-Onset Parkinson’s Disease in a Chinese Cohort. (PMID:32662538)
• Inhibiting calpain 1 and 2 in cyclin G associated kinase-knockout mice mitigates podocyte injury. (PMID:33208557)
• GAK and PRKCD are positive regulators of PRKN-independent mitophagy. (PMID:34671015)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gak	ENSDARG00000090654
mus_musculus	Gak	ENSMUSG00000062234
rattus_norvegicus	Gak	ENSRNOG00000000048
drosophila_melanogaster	aux	FBGN0037218
caenorhabditis_elegans		WBGENE00001043

Paralogs (1): DNAJC6 (ENSG00000116675)

Protein

Protein identifiers

Cyclin-G-associated kinase — O14976 (reviewed: O14976)

Alternative names: DnaJ homolog subfamily C member 26

All UniProt accessions (9): O14976, D6RAQ7, D6RAW3, D6RC24, D6RE78, D6RF16, H0Y8H5, H0Y9M4, H0YA39

UniProt curated annotations — full annotation on UniProt →

Function. Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1. May play a role in clathrin-mediated endocytosis and intracellular trafficking, and in the dynamics of clathrin assembly/disassembly.

Subcellular location. Cytoplasm. Perinuclear region. Golgi apparatus. trans-Golgi network. Cell junction. Focal adhesion. Cytoplasmic vesicle. Clathrin-coated vesicle.

Tissue specificity. Ubiquitous. Highest in testis.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O14976-1	1	yes
O14976-2	2

RefSeq proteins (2): NP_001305063, NP_005246* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001623	DnaJ_domain	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR014020	Tensin_C2-dom	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR029023	Tensin_phosphatase	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036869	J_dom_sf	Homologous_superfamily

Pfam: PF00069, PF10409

Catalyzed reactions (Rhea), 2 shown:

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

UniProt features (77 total): modified residue 17, helix 14, sequence variant 11, strand 10, compositionally biased region 6, region of interest 5, domain 4, turn 4, sequence conflict 2, initiator methionine 1, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4O38	X-RAY DIFFRACTION	2.1
4Y8D	X-RAY DIFFRACTION	2.1
4C58	X-RAY DIFFRACTION	2.16
5Y80	X-RAY DIFFRACTION	2.5
4C57	X-RAY DIFFRACTION	2.55
4C59	X-RAY DIFFRACTION	2.8
5Y7Z	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14976-F1	67.32	0.36

Antibody-complex structures (SAbDab): 6 — 4C57, 4C58, 4C59, 4Y8D, 5Y7Z, 5Y80

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): 173 (proton acceptor)

Post-translational modifications (17): 2, 2, 16, 456, 770, 776, 783, 794, 811, 826, 829, 834, 939, 1096, 1123, 1176, 1185

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-8856828	Clathrin-mediated endocytosis

MSigDB gene sets: 183 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE45365_NK_CELL_VS_BCELL_UP, GOBP_LYSOSOMAL_TRANSPORT, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_VACUOLAR_TRANSPORT, GOBP_NEUROGENESIS, CREBP1_Q2, GOBP_CLATHRIN_COAT_ASSEMBLY, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_SYNAPTIC_VESICLE_RECYCLING, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, CREB_Q4

GO Biological Process (15): protein folding (GO:0006457), receptor-mediated endocytosis (GO:0006898), endoplasmic reticulum organization (GO:0007029), Golgi organization (GO:0007030), negative regulation of neuron projection development (GO:0010977), synaptic vesicle uncoating (GO:0016191), protein localization to Golgi apparatus (GO:0034067), intracellular transport (GO:0046907), clathrin coat assembly (GO:0048268), clathrin coat disassembly (GO:0072318), clathrin-dependent endocytosis (GO:0072583), protein localization to plasma membrane (GO:0072659), Golgi to lysosome transport (GO:0090160), regulation of clathrin coat assembly (GO:1905443), protein phosphorylation (GO:0006468)

GO Molecular Function (11): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), clathrin binding (GO:0030276), cyclin binding (GO:0030332), protein folding chaperone (GO:0044183), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (11): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), focal adhesion (GO:0005925), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136), vesicle (GO:0031982), perinuclear region of cytoplasm (GO:0048471), presynapse (GO:0098793), cytoplasmic vesicle (GO:0031410), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
organelle organization	2
endomembrane system organization	2
intracellular anatomical structure	2
protein kinase activity	2
protein binding	2
cellular process	1
protein maturation	1
endocytosis	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
synaptic vesicle endocytosis	1
clathrin coat disassembly	1
protein localization to organelle	1
transport	1
cellular localization	1
establishment of localization in cell	1
protein-containing complex assembly	1
vesicle uncoating	1
clathrin-dependent endocytosis	1
receptor-mediated endocytosis	1
protein localization to membrane	1
protein localization to cell periphery	1
Golgi to vacuole transport	1
lysosomal transport	1
cytosolic transport	1
regulation of protein-containing complex assembly	1
clathrin coat assembly	1
phosphorylation	1
protein modification process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
molecular_function	1
protein folding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1

Protein interactions and networks

STRING

5448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GAK	RAB29	O14966	971
GAK	LRRK2	Q5S007	953
GAK	CCNG1	P51959	944
GAK	BAG5	Q9UL15	912
GAK	CLTCL1	P53675	826
GAK	VPS35	Q96QK1	816
GAK	HSPA8	P11142	816
GAK	CLTC	Q00610	813
GAK	GBA1	P04062	770
GAK	CDK5	Q00535	754
GAK	TMEM175	Q9BSA9	728
GAK	HIP1R	O75146	717
GAK	DGKQ	P52824	707
GAK	CCDC62	Q6P9F0	700
GAK	MCCC1	Q96RQ3	690

IntAct

148 interactions, top by confidence:

A	B	Type	Score
PALS1	LIN7A	psi-mi:“MI:0914”(association)	0.870
GAK	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.790
LRRK2	GAK	psi-mi:“MI:0407”(direct interaction)	0.790
GAK	LRRK2	psi-mi:“MI:0915”(physical association)	0.790
GAK	LRRK2	psi-mi:“MI:0914”(association)	0.790
GAK	LRRK2	psi-mi:“MI:0403”(colocalization)	0.790
LRRK2	GAK	psi-mi:“MI:0403”(colocalization)	0.790
HSPA8	GAK	psi-mi:“MI:0914”(association)	0.760
GAK	HSPA8	psi-mi:“MI:0914”(association)	0.760
HSPA8	GAK	psi-mi:“MI:0915”(physical association)	0.760
STAMBP	PIK3C2A	psi-mi:“MI:0914”(association)	0.730
HIP1R	HIP1	psi-mi:“MI:0914”(association)	0.640
STAMBPL1	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
GPX7	GAK	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
FAM174A	GAK	psi-mi:“MI:0914”(association)	0.640
GAK	RAM2	psi-mi:“MI:0915”(physical association)	0.560
RAM2	GAK	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (242): GAK (Affinity Capture-MS), GAK (Affinity Capture-MS), USO1 (Two-hybrid), GAK (Affinity Capture-MS), PPM1B (Co-fractionation), AP2A1 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP2B1 (Affinity Capture-MS), CALM1 (Affinity Capture-MS), CALML3 (Affinity Capture-MS), CAPZB (Affinity Capture-MS), AP2M1 (Affinity Capture-MS), CLTA (Affinity Capture-MS), CLTB (Affinity Capture-MS), CLTC (Affinity Capture-MS)

ESM2 similar proteins: A0AVI2, A0FGR9, A2AP18, A3KGK3, A6QQP7, F1LYQ8, F8VPU2, O00329, O08835, O14976, O15068, O35904, O75038, O75923, O94887, P19687, P40749, P50232, P58069, P97610, P97874, Q14644, Q15283, Q28013, Q5DTI8, Q5FWL4, Q5M7N9, Q5RAB8, Q5RJH2, Q60790, Q63406, Q63713, Q64096, Q6DN12, Q6P7F1, Q7L8C5, Q7ZWU7, Q8IV01, Q8VHQ7, Q91VS8

Diamond homologs: E9Q0S6, G5EE01, H2L045, O08586, O14976, O54857, P60483, P60484, P97874, Q04205, Q32PJ7, Q4R6N0, Q4V8I3, Q54JL7, Q5SSZ5, Q63HR2, Q68CZ2, Q6NR09, Q8BZ33, Q8CGB6, Q8H106, Q8IZW8, Q8T9S7, Q99KY4, Q9FLZ5, Q9GLM4, Q9HBL0, Q9LT75, Q9PUT6, A2X6X1, A5A7I8, A8WRV1, F1MH24, F1SPM8, F4I4F2, G5ECQ3, O13839, O34507, O43066, O75716

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GAK	“up-regulates activity”	CLTC	phosphorylation
SRC	“up-regulates activity”	GAK	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 139 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
Lysosome Vesicle Biogenesis	6	21.1×	5e-05
Golgi Associated Vesicle Biogenesis	9	19.4×	2e-07
Clathrin-mediated endocytosis	15	13.8×	1e-10
Cargo recognition for clathrin-mediated endocytosis	9	10.1×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
clathrin coat assembly	6	45.5×	2e-06
clathrin-dependent endocytosis	5	24.8×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	226
Likely benign	18
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

6125 predictions. Top by Δscore:

Variant	Effect	Δscore
4:849771:CAGC:C	acceptor_gain	1.0000
4:849772:AGCC:A	acceptor_loss	1.0000
4:849773:GCC:G	acceptor_loss	1.0000
4:849887:CTCA:C	donor_loss	1.0000
4:849888:TCACC:T	donor_loss	1.0000
4:849889:CACC:C	donor_loss	1.0000
4:849890:A:AC	donor_gain	1.0000
4:849890:AC:A	donor_gain	1.0000
4:849890:ACCT:A	donor_loss	1.0000
4:849891:C:CA	donor_gain	1.0000
4:849891:CC:C	donor_gain	1.0000
4:849891:CCTTG:C	donor_gain	1.0000
4:850069:C:CC	acceptor_gain	1.0000
4:865116:CCATA:C	donor_loss	1.0000
4:865117:CATA:C	donor_loss	1.0000
4:865118:ATAC:A	donor_loss	1.0000
4:865119:TAC:T	donor_loss	1.0000
4:865120:A:AT	donor_loss	1.0000
4:865121:C:G	donor_loss	1.0000
4:865121:CCTT:C	donor_gain	1.0000
4:865240:ATCCC:A	acceptor_gain	1.0000
4:865241:TCCC:T	acceptor_gain	1.0000
4:865242:CCC:C	acceptor_gain	1.0000
4:865242:CCCC:C	acceptor_gain	1.0000
4:865243:CC:C	acceptor_gain	1.0000
4:865243:CCC:C	acceptor_gain	1.0000
4:865244:CC:C	acceptor_gain	1.0000
4:865244:CCT:C	acceptor_loss	1.0000
4:865245:C:CA	acceptor_loss	1.0000
4:865245:C:CC	acceptor_gain	1.0000

AlphaMissense

8566 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:870896:A:G	L688P	1.000
4:883364:A:T	V452D	1.000
4:898112:T:A	D191V	1.000
4:898112:T:G	D191A	1.000
4:849725:A:G	L1295P	0.999
4:849927:A:C	Y1267D	0.999
4:849981:A:G	W1249R	0.999
4:849981:A:T	W1249R	0.999
4:850059:A:G	W1223R	0.999
4:850059:A:T	W1223R	0.999
4:870712:A:C	F749L	0.999
4:870712:A:T	F749L	0.999
4:870714:A:G	F749L	0.999
4:870857:A:G	F701S	0.999
4:876536:A:G	F683S	0.999
4:877688:A:G	C595R	0.999
4:877714:G:T	P586Q	0.999
4:881909:T:A	K553N	0.999
4:881909:T:G	K553N	0.999
4:881948:G:C	S540R	0.999
4:881948:G:T	S540R	0.999
4:881950:T:G	S540R	0.999
4:881952:A:G	F539S	0.999
4:881964:G:T	A535D	0.999
4:881985:A:G	L528P	0.999
4:882008:G:C	C520W	0.999
4:882021:G:T	A516D	0.999
4:882037:C:A	G511W	0.999
4:882710:A:T	V505D	0.999
4:882737:A:G	L496P	0.999

dbSNP variants (sampled 300 via entrez): RS1000012919 (4:923033 A>G), RS1000023694 (4:887167 C>T), RS1000028500 (4:905103 G>T), RS1000054784 (4:887220 C>A,T), RS1000129773 (4:849019 GGAGA>G,GGA), RS1000147303 (4:864132 A>G), RS1000150759 (4:925477 G>A), RS1000171964 (4:865337 C>A,T), RS1000174097 (4:864451 G>C,T), RS1000206365 (4:919388 A>C), RS1000208730 (4:890748 G>A,T), RS1000285444 (4:860965 A>G), RS1000313617 (4:924636 C>A), RS1000320457 (4:913080 C>T), RS1000340241 (4:894586 G>A,C)

Disease associations

OMIM: gene MIM:602052 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000261_1	Parkinson’s disease (familial)	7.000000e-07
GCST000772_2	Parkinson’s disease	3.000000e-09
GCST000959_1	Parkinson’s disease	4.000000e-12
GCST001126_5	Parkinson’s disease	4.000000e-08
GCST001445_3	Parkinson’s disease	3.000000e-12
GCST002544_16	Parkinson’s disease	1.000000e-43
GCST003129_30	Primary biliary cholangitis	9.000000e-12
GCST003817_6	Mortality in sepsis	2.000000e-06
GCST003984_22	Parkinson’s disease	3.000000e-15
GCST006611_105	HDL cholesterol	2.000000e-08
GCST006613_24	Triglycerides	1.000000e-11
GCST007780_3	Parkinson’s disease (age of onset)	1.000000e-08
GCST009325_97	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	2.000000e-21
GCST010049_9	Parkinson’s disease	7.000000e-06
GCST90020024_1233	A body shape index	3.000000e-09
GCST90020024_1234	A body shape index	6.000000e-09
GCST90020025_1042	Waist-to-hip ratio adjusted for BMI	1.000000e-10
GCST90020025_1044	Waist-to-hip ratio adjusted for BMI	8.000000e-10
GCST90020027_1865	Waist-hip index	2.000000e-10
GCST90020027_1867	Waist-hip index	2.000000e-09
GCST90020029_729	Waist circumference adjusted for body mass index	3.000000e-09
GCST90020029_730	Waist circumference adjusted for body mass index	3.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004352	mortality
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004847	age at onset
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL4355 (SINGLE PROTEIN), CHEMBL4748217 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465204 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

77 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 190,706 (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
CHEMBL1078178	MOMELOTINIB	4	3,481
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1738797	ALECTINIB	4	6,731
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2105712	AFATINIB DIMALEATE	4	3,215
CHEMBL2105759	BARICITINIB	4	6,741
CHEMBL2110732	DACOMITINIB ANHYDROUS	4	6,578
CHEMBL2396661	ALPELISIB	4	6,070
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3545110	RIBOCICLIB	4	8,018
CHEMBL3622821	UPADACITINIB	4	2,726
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL535	SUNITINIB	4
CHEMBL5416410	DASATINIB	4
CHEMBL553	ERLOTINIB	4
CHEMBL608533	MIDOSTAURIN	4
CHEMBL939	GEFITINIB	4
CHEMBL941	IMATINIB	4
CHEMBL2087361	ICOTINIB	3
CHEMBL2105728	CRENOLANIB	3
CHEMBL217092	SARACATINIB	3
CHEMBL223360	LINIFANIB	3

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Numb-associated kinase (NAK) family

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

Ligand	Action	Affinity	Parameter
SB203580	Inhibition	6.87	pIC50
baricitinib	Inhibition	6.87	pKd

Binding affinities (BindingDB)

21 measured of 21 human assays (21 total across all organisms); most potent 21 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole	KD	9.8 nM
4-[4-(4-fluorophenyl)-2-(4-methanesulfinylphenyl)-1H-imidazol-5-yl]pyridine	KD	12 nM
BMS-354825	KD	27 nM
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
PKC-412	KD	190 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide	KD	1000 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
ERLOTINIB HYDROCHLORIDE	KD	1200 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
CI-1033	KD	1700 nM
BMS-387072	KD	1800 nM
GEFITINIB	IC50	2300 nM	US-9416123: Kinase modulators for the treatment of cancer
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
(E)-N-[4-(3-chloro-4-fluoro-anilino)-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide	KD	3500 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM

ChEMBL bioactivities

472 potent at pChembl≥5 of 479 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	IC50	0.06	nM	CHEMBL4531690
9.52	Kd	0.3	nM	BMS-690514
9.38	Kd	0.42	nM	CHEMBL81073
9.00	IC50	1	nM	FEDRATINIB
9.00	Kd	1	nM	CHEMBL5415503
8.96	Kd	1.1	nM	FEDRATINIB
8.89	Kd	1.3	nM	BOSUTINIB
8.82	Kd	1.5	nM	PELITINIB
8.82	Ki	1.5	nM	CHEMBL4797973
8.72	Kd	1.9	nM	CHEMBL4443342
8.70	Kd	2	nM	CHEMBL400402
8.66	IC50	2.2	nM	CHEMBL4740761
8.62	IC50	2.4	nM	CHEMBL81073
8.59	Kd	2.6	nM	DASATINIB
8.59	Kd	2.6	nM	CHEMBL4440586
8.54	Kd	2.9	nM	CHEMBL311959
8.52	Kd	3	nM	MILCICLIB
8.51	Kd	3.1	nM	ERLOTINIB
8.51	Ki	3.1	nM	CHEMBL4443342
8.51	Kd	3.1	nM	CHEMBL4443342
8.49	IC50	3.2	nM	CHEMBL4778276
8.42	Ki	3.8	nM	CHEMBL4531690
8.42	IC50	3.8	nM	CHEMBL4762694
8.41	Kd	3.9	nM	CHEMBL4585158
8.40	Kd	4	nM	RGB-286638
8.39	Kd	4.1	nM	CHEMBL4443342
8.35	Kd	4.5	nM	CHEMBL4443342
8.31	Kd	4.9	nM	CHEMBL4585158
8.31	Kd	4.9	nM	CHEMBL4781252
8.30	Kd	5	nM	CHEMBL3688339
8.30	Kd	5	nM	CHEMBL5566270
8.28	Kd	5.3	nM	TAE-684
8.21	Kd	6.2	nM	CHEMBL5574808
8.20	Kd	6.3	nM	CHEMBL4556662
8.19	Kd	6.4	nM	PELITINIB
8.17	Kd	6.8	nM	CHEMBL304929
8.17	Kd	6.7	nM	CHEMBL4556662
8.15	Kd	7	nM	GEFITINIB
8.14	Kd	7.3	nM	LESTAURTINIB
8.13	Kd	7.4	nM	CHEMBL5565547
8.12	Kd	7.6	nM	CHEMBL1092250
8.12	Kd	7.6	nM	CHEMBL4740155
8.11	IC50	7.7	nM	CHEMBL4764705
8.10	Kd	7.9	nM	CHEMBL4517424
8.09	Kd	8.2	nM	CHEMBL386051
8.08	Kd	8.3	nM	CHEMBL3425865
8.07	Kd	8.6	nM	CHEMBL4517424
8.07	Kd	8.6	nM	CHEMBL4782290
8.06	IC50	8.8	nM	CHEMBL4794323
8.05	Kd	8.9	nM	CHEMBL3425867

PubChem BioAssay actives

455 with measured affinity, of 1075 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
4-chloro-7,10-dioxa-13,17,18,21-tetrazatetracyclo[12.5.2.12,6.017,20]docosa-1(20),2(22),3,5,14(21),15,18-heptaene	1638760: Displacement of fluorescent tracer from N-terminus of human GAK expressed in HEK293T cells after 2 hrs by NanoBRET target engagement assay	ic50	0.0001	uM
(3R,4R)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol	1425009: 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	0.0003	uM
6,7-dimethoxy-4-(3,4,5-trimethoxyanilino)quinoline-3-carbonitrile	1595619: Binding affinity to wild-type human partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by Kinomescan method	kd	0.0004	uM
Fedratinib	1875914: Inhibition of GAK (unknown origin)	ic50	0.0010	uM
N-[3-[2-[2-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	1988541: Binding affinity to GAK (unknown origin) assessed as dissociation constant by KINOME scan assay	kd	0.0010	uM
Bosutinib	1595619: Binding affinity to wild-type human partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by Kinomescan method	kd	0.0013	uM
7-pyridin-4-yl-3-(3,4,5-trimethoxyphenyl)quinoline	1673307: Binding affinity to GAK (unknown origin)	ki	0.0015	uM
(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide	256612: Average Binding Constant for GAK; NA=Not Active at 10 uM	kd	0.0015	uM
6-bromo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638748: Binding affinity to biotinylated human GAK (13 to 338 residues) expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.0019	uM
4-chloro-3-[5-methyl-3-[4-(2-pyrrolidin-1-ylethoxy)anilino]-1,2,4-benzotriazin-7-yl]phenol	1425009: 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	0.0020	uM
N-[3-[6-(4-amino-3-methoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]phenyl]pyrrolidine-1-carboxamide	1730898: Inhibition of tracer 222 binding to GAK (unknown origin) incubated for 1 hr by Lanthascreen TR-FRET assay	ic50	0.0022	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	1205944: Binding affinity to human GAK fused to T7 bacteriophage expressed in Escherichia coli BL21 after 1 hr by qPCR analysis	kd	0.0026	uM
4-(3-ethynylanilino)-6,7-dimethoxyquinoline-3-carbonitrile	1595619: Binding affinity to wild-type human partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by Kinomescan method	kd	0.0026	uM
6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638748: Binding affinity to biotinylated human GAK (13 to 338 residues) expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.0029	uM
N,1,4,4-tetramethyl-8-[4-(4-methylpiperazin-1-yl)anilino]-5H-pyrazolo[4,5-h]quinazoline-3-carboxamide	1425009: 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	0.0030	uM
Erlotinib	1205970: Binding affinity to human GAK fused to T7 bacteriophage after 1 hr by qPCR analysis	kd	0.0031	uM
N-[3-[6-(4-amino-3-methoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]phenyl]morpholine-4-carboxamide	1730898: Inhibition of tracer 222 binding to GAK (unknown origin) incubated for 1 hr by Lanthascreen TR-FRET assay	ic50	0.0032	uM
N-[3-[6-(4-amino-3-methoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]phenyl]-2-methylpropanamide	1730898: Inhibition of tracer 222 binding to GAK (unknown origin) incubated for 1 hr by Lanthascreen TR-FRET assay	ic50	0.0038	uM
4-(3,4,5-trimethoxyanilino)quinoline-6-carbonitrile	1638748: Binding affinity to biotinylated human GAK (13 to 338 residues) expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.0039	uM
1-[3-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]phenyl]-4-oxo-1H-indeno[2,1-d]pyrazol-5-yl]-3-morpholin-4-ylurea	1425009: 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	0.0040	uM
N-(3-methoxyphenyl)-6-(trifluoromethyl)quinolin-4-amine	1673288: Binding affinity to human wild type partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by KinomeScan method	kd	0.0049	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425009: 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	0.0050	uM
6-(4-fluoro-3-methoxyphenyl)-15-(2-methoxyethoxy)-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110399: Binding affinity to recombinant his tagged GAK (unknown origin) assessed as dissociation constant by surface plasmon resonance method	kd	0.0050	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625012: Binding constant for GAK kinase domain	kd	0.0053	uM
6-(4-fluoro-3-methoxyphenyl)-15-methoxy-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110399: Binding affinity to recombinant his tagged GAK (unknown origin) assessed as dissociation constant by surface plasmon resonance method	kd	0.0062	uM
6-chloro-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1673288: Binding affinity to human wild type partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by KinomeScan method	kd	0.0063	uM
N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine	1595619: Binding affinity to wild-type human partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by Kinomescan method	kd	0.0068	uM
Gefitinib	256612: Average Binding Constant for GAK; NA=Not Active at 10 uM	kd	0.0070	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507961: Binding affinity to GAK	kd	0.0073	uM
6-(4-fluoro-3-methoxyphenyl)-13lambda6-thia-2,4,8,12,19-pentazatricyclo[12.3.1.13,7]nonadeca-1(18),3,5,7(19),14,16-hexaene 13,13-dioxide	2110399: Binding affinity to recombinant his tagged GAK (unknown origin) assessed as dissociation constant by surface plasmon resonance method	kd	0.0074	uM
7-iodo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1673288: Binding affinity to human wild type partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by KinomeScan method	kd	0.0076	uM
N-(3-ethynylphenyl)-6,7-dimethoxyquinolin-4-amine	1595619: Binding affinity to wild-type human partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by Kinomescan method	kd	0.0076	uM
N-[3-[6-(4-amino-3-methoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]phenyl]propanamide	1730898: Inhibition of tracer 222 binding to GAK (unknown origin) incubated for 1 hr by Lanthascreen TR-FRET assay	ic50	0.0077	uM
6-iodo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1638748: Binding affinity to biotinylated human GAK (13 to 338 residues) expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.0079	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	625012: Binding constant for GAK kinase domain	kd	0.0082	uM
4-[6-(3,4,5-trimethoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]morpholine	1205944: Binding affinity to human GAK fused to T7 bacteriophage expressed in Escherichia coli BL21 after 1 hr by qPCR analysis	kd	0.0083	uM
7-bromo-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1673288: Binding affinity to human wild type partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by KinomeScan method	kd	0.0086	uM
N-[3-[6-(4-amino-3-methoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]phenyl]cyclopropanecarboxamide	1730898: Inhibition of tracer 222 binding to GAK (unknown origin) incubated for 1 hr by Lanthascreen TR-FRET assay	ic50	0.0088	uM
2-methoxy-4-(3-morpholin-4-yl-[1,2]thiazolo[4,3-b]pyridin-6-yl)aniline	1205944: Binding affinity to human GAK fused to T7 bacteriophage expressed in Escherichia coli BL21 after 1 hr by qPCR analysis	kd	0.0089	uM
Gilteritinib	1425009: 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	0.0090	uM
4-(3,4,5-trimethoxyanilino)quinoline-7-carbonitrile	1638748: Binding affinity to biotinylated human GAK (13 to 338 residues) expressed in Escherichia coli incubated for 1.5 hrs by fluorescent tracer dependent TR-FRET based competitive ligand binding displacement assay	kd	0.0097	uM
6-(trifluoromethyl)-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1673288: Binding affinity to human wild type partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by KinomeScan method	kd	0.0100	uM
Alectinib	1700713: Inhibition of human GAK	ic50	0.0100	uM
6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinazolin-4-amine	1595619: Binding affinity to wild-type human partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by Kinomescan method	kd	0.0100	uM
4-[3-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-[1,2]thiazolo[4,3-b]pyridin-6-yl]-2-methoxyaniline	1350709: Binding affinity to DNA-tagged human GAK expressed in Escherichia coli BL21 using immobilised ligand incubated for 1 hr by quantitative PCR	kd	0.0110	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	1730898: Inhibition of tracer 222 binding to GAK (unknown origin) incubated for 1 hr by Lanthascreen TR-FRET assay	ic50	0.0110	uM
N-[3-[6-(4-amino-3-methoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]phenyl]prop-2-enamide	1730898: Inhibition of tracer 222 binding to GAK (unknown origin) incubated for 1 hr by Lanthascreen TR-FRET assay	ic50	0.0120	uM
4-(3-bromoanilino)-6,7-dimethoxyquinoline-3-carbonitrile	1595619: Binding affinity to wild-type human partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by Kinomescan method	kd	0.0120	uM
7-chloro-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine	1673288: Binding affinity to human wild type partial length GAK (G13 to Y338 residues) expressed in bacterial expression system by KinomeScan method	kd	0.0130	uM
N-[[(3R)-1-[6-(4-amino-3-methoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]piperidin-3-yl]methyl]cyclopropanecarboxamide	1730898: Inhibition of tracer 222 binding to GAK (unknown origin) incubated for 1 hr by Lanthascreen TR-FRET assay	ic50	0.0130	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	3
sodium arsenite	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
baricitinib	decreases activity	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
benzo(e)pyrene	increases methylation	1
4-hydroxy-2-nonenal	decreases expression	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects expression, affects methylation	1
Ascorbic Acid	decreases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1

ChEMBL screening assays

263 unique, capped per target: 260 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004484	Binding	Binding affinity to human recombinant GAK expressed in Escherichia coli assessed as thermal shift by differential scanning fluorimetry	Discovery of a potent and selective inhibitor for human carbonyl reductase 1 from propionate scanning applied to the macrolide zearalenone. — Bioorg Med Chem
CHEMBL5210023	Functional	Affinity Phenotypic Cellular interaction (Cell viability assay (CellTiter-Glo assay (Promega); 22Rv1 prostate cancer cell line)) EUB0000207b GAK	Affinity Phenotypic Cellular Literature for EUbOPEN Chemogenomics Library wave 3

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2XJ	Abcam HEK293T GAK KO	Transformed cell line	Female
CVCL_E0DP	Ubigene HeLa GAK KO	Cancer cell line	Female
CVCL_SP48	HAP1 GAK (-) 1	Cancer cell line	Male
CVCL_SP49	HAP1 GAK (-) 2	Cancer cell line	Male
CVCL_SP50	HAP1 GAK (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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