GCK

Summary

GCK (glucokinase, HGNC:4195) is a protein-coding gene on chromosome 7p13, encoding Hexokinase-4 (P35557). Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively). It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia.

Source: NCBI Gene 2645 — RefSeq curated summary.

At a glance

• Gene–disease (curated): monogenic diabetes (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 47 (top 2% of genes corpus-wide)
• Clinical variants (ClinVar): 1,416 total — 344 pathogenic, 301 likely-pathogenic (top 2% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈5% of expected missense variation)
• GTEx eGene: eQTL in 31 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 80
• Drug target: yes — 6 curated mechanism-of-action drugs; 5 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.87 (unconstrained)
• MANE Select transcript: NM_000162
• Interaction hub: 1,750 STRING partners (top 10% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4195
Approved symbol	GCK
Name	glucokinase
Location	7p13
Locus type	gene with protein product
Status	Approved
Aliases	HK4, HKIV
Ensembl gene	ENSG00000106633
Ensembl biotype	protein_coding
OMIM	138079
Entrez	2645

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

MANE Select: ENST00000403799

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

ENST00000403799, ENST00000336642, ENST00000345378, ENST00000395796, ENST00000437084, ENST00000459642, ENST00000473353, ENST00000476008, ENST00000616242, ENST00000671824, ENST00000672743, ENST00000673284, ENST00000682635, ENST00000683378

RefSeq mRNA: 6 — MANE Select: NM_000162 NM_000162, NM_001354800, NM_001354801, NM_001354803, NM_033507, NM_033508

CCDS: CCDS5479, CCDS5480, CCDS94091, CCDS94092

Canonical transcript exons

ENST00000403799 — 10 exons

Exon	Start	End
ENSE00000680807	44149969	44150064
ENSE00000680809	44150956	44151075
ENSE00000680812	44153301	44153463
ENSE00000832574	44145497	44145730
ENSE00000832576	44147650	44147833
ENSE00000832577	44149760	44149859
ENSE00000832580	44152271	44152425
ENSE00001362239	44188909	44189439
ENSE00001689304	44144275	44145280
ENSE00003605854	44146463	44146618

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 88.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4009 / max 439.2052, expressed in 31 samples.

Highest expression (Bgee): pituitary gland, adenohypophysis, islet of Langerhans, atrium auricular region, hemisphere of cerebellum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

GCK is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 31 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 34 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	3.3e-25	-0.43	7:44146206:C:G
Esophagus Muscularis	eqtl	4.4e-25	-0.48	7:44146206:C:G
Skin Sun Exposed Lower leg	eqtl	8.7e-18	-0.38	7:44146206:C:G
Heart Atrial Appendage	eqtl	1.3e-17	-0.37	7:44146206:C:G
Thyroid	eqtl	1.2e-16	+0.40	7:44186502:C:T
Artery Tibial	eqtl	2.3e-16	+0.35	7:44143834:G:A
Lung	eqtl	2.8e-15	-0.35	7:44134572:C:T
Adipose Subcutaneous	eqtl	4.3e-14	-0.35	7:44146206:C:G
Esophagus Gastroesophageal Junction	eqtl	1.9e-13	-0.43	7:44146206:C:G
Spleen	eqtl	1.6e-12	-0.58	7:44146206:C:G
Cells Cultured fibroblasts	eqtl	2.1e-12	+0.34	7:44149675:T:C
Artery Aorta	eqtl	6.7e-11	-0.27	7:44134572:C:T
Breast Mammary Tissue	eqtl	1.3e-10	+0.34	7:44132679:A:G
Colon Sigmoid	eqtl	1.9e-08	+0.47	7:44143834:G:A
Ovary	eqtl	2.3e-08	-0.58	7:44143527:C:G
Heart Left Ventricle	eqtl	3.2e-08	-0.36	7:44148510:GT:G
Adipose Visceral Omentum	eqtl	3.6e-08	+0.43	7:44139144:C:T
Skin Not Sun Exposed Suprapubic	eqtl	4.6e-06	-0.26	7:44130986:G:A
Artery Coronary	eqtl	2.0e-04	-0.36	7:44095611:CTG:C
Heart Atrial Appendage	sqtl	7.6e-04	-3.20	7:44762564:G:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
83856	0.3742	22
83854	0.0177	7
204425	0.0090	3

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	88.54	gold quality
adenohypophysis	UBERON:0002196	88.35	gold quality
islet of Langerhans	UBERON:0000006	82.30	gold quality
right atrium auricular region	UBERON:0006631	80.21	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.36	gold quality
cerebellar hemisphere	UBERON:0002245	78.25	gold quality
cardiac atrium	UBERON:0002081	78.12	gold quality
cerebellar cortex	UBERON:0002129	77.95	gold quality
hypothalamus	UBERON:0001898	77.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.47	silver quality
cerebellum	UBERON:0002037	76.16	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.10	gold quality
right frontal lobe	UBERON:0002810	74.20	gold quality
cingulate cortex	UBERON:0003027	73.98	gold quality
anterior cingulate cortex	UBERON:0009835	73.81	gold quality
amygdala	UBERON:0001876	73.63	gold quality
prefrontal cortex	UBERON:0000451	73.31	gold quality
nucleus accumbens	UBERON:0001882	72.77	gold quality
Brodmann (1909) area 9	UBERON:0013540	72.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	71.58	gold quality
cortical plate	UBERON:0005343	71.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	71.27	gold quality
right lobe of liver	UBERON:0001114	70.38	gold quality
ascending aorta	UBERON:0001496	70.32	gold quality
apex of heart	UBERON:0002098	70.27	gold quality
thoracic aorta	UBERON:0001515	70.25	gold quality
brain	UBERON:0000955	70.23	gold quality
central nervous system	UBERON:0001017	70.21	gold quality
forebrain	UBERON:0001890	70.16	gold quality
popliteal artery	UBERON:0002250	70.07	gold quality
aorta	UBERON:0000947	70.06	gold quality
tibial artery	UBERON:0007610	70.06	gold quality
neocortex	UBERON:0001950	69.91	gold quality
spinal cord	UBERON:0002240	69.77	gold quality
frontal cortex	UBERON:0001870	69.70	gold quality
caudate nucleus	UBERON:0001873	69.53	gold quality
substantia nigra	UBERON:0002038	69.24	gold quality
right coronary artery	UBERON:0001625	69.19	gold quality
endocervix	UBERON:0000458	69.14	gold quality
descending thoracic aorta	UBERON:0002345	69.14	gold quality
pancreas	UBERON:0001264	69.04	gold quality
heart	UBERON:0000948	69.00	gold quality
putamen	UBERON:0001874	68.47	gold quality
midbrain	UBERON:0001891	68.10	gold quality
telencephalon	UBERON:0001893	68.05	gold quality
left coronary artery	UBERON:0001626	68.03	gold quality
cerebral cortex	UBERON:0000956	68.02	gold quality
coronary artery	UBERON:0001621	67.41	gold quality
ectocervix	UBERON:0012249	66.78	gold quality
temporal lobe	UBERON:0001871	66.17	gold quality
heart left ventricle	UBERON:0002084	66.17	gold quality
cardiac ventricle	UBERON:0002082	65.77	gold quality
Ammon’s horn	UBERON:0001954	65.53	gold quality
body of uterus	UBERON:0009853	65.17	gold quality
stromal cell of endometrium	CL:0002255	65.16	gold quality
right ovary	UBERON:0002118	64.87	gold quality
lateral nuclear group of thalamus	UBERON:0002736	64.59	gold quality
type B pancreatic cell	CL:0000169	64.19	gold quality
left ovary	UBERON:0002119	64.18	gold quality
body of pancreas	UBERON:0001150	63.39	gold quality
Brodmann (1909) area 46	UBERON:0006483	62.60	gold quality
vagina	UBERON:0000996	62.47	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	62.19	gold quality
uterine cervix	UBERON:0000002	61.94	gold quality
liver	UBERON:0002107	61.78	gold quality
upper arm skin	UBERON:0004263	61.44	gold quality
pons	UBERON:0000988	61.28	silver quality
tibial nerve	UBERON:0001323	61.04	gold quality
secondary oocyte	CL:0000655	61.00	gold quality
lower esophagus muscularis layer	UBERON:0035833	60.86	gold quality
endometrium epithelium	UBERON:0004811	60.81	gold quality
lower esophagus	UBERON:0013473	60.81	gold quality
substantia nigra pars compacta	UBERON:0001965	60.50	gold quality
ovary	UBERON:0000992	60.41	gold quality
left uterine tube	UBERON:0001303	59.76	gold quality
ganglionic eminence	UBERON:0004023	59.70	gold quality
fundus of stomach	UBERON:0001160	59.43	gold quality
parotid gland	UBERON:0001831	58.81	gold quality
dorsal plus ventral thalamus	UBERON:0001897	58.71	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	58.40	gold quality
placenta	UBERON:0001987	57.84	gold quality
superior frontal gyrus	UBERON:0002661	57.79	gold quality
esophagus	UBERON:0001043	57.74	gold quality
female reproductive system	UBERON:0000474	57.65	gold quality
ventral tegmental area	UBERON:0002691	57.64	gold quality
mucosa of stomach	UBERON:0001199	57.56	gold quality
medulla oblongata	UBERON:0001896	57.56	gold quality
subthalamic nucleus	UBERON:0001906	57.55	gold quality
omental fat pad	UBERON:0010414	57.55	gold quality
peritoneum	UBERON:0002358	57.54	gold quality
seminal vesicle	UBERON:0000998	57.45	gold quality
anatomical system	UBERON:0000467	57.22	gold quality
cranial nerve II	UBERON:0000941	57.12	silver quality
cartilage tissue	UBERON:0002418	56.96	gold quality
multicellular organism	UBERON:0000468	56.92	gold quality
material anatomical entity	UBERON:0000465	56.90	gold quality
myometrium	UBERON:0001296	56.88	gold quality
superior vestibular nucleus	UBERON:0007227	56.82	gold quality
inferior olivary complex	UBERON:0002127	56.74	gold quality
primary visual cortex	UBERON:0002436	56.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	6.50
E-ANND-3	no	2.74

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pituitary gland	tissue	19.5
Hypothalamus	tissue	10.8
Cerebellum	tissue	9.0	medium
Septum	tissue	8.2
Substantia nigra	tissue	7.6
Periaqueductal gray	tissue	7.3
Cerebral cortex	tissue	7.0	high
Amygdala	tissue	7.0
Olfactory bulb	tissue	7.0
Insular cortex	tissue	7.0
Basal ganglia	tissue	6.8	medium
Hippocampal formation	tissue	6.8
Spinal cord	tissue	6.6
Ventral forebrain	tissue	6.6
Pons	tissue	6.4
Corpus callosum	tissue	6.3
Midbrain	tissue	6.2
Retrosplenial and cingulate cortex	tissue	6.0
Retrosplenial cortex	tissue	6.0
Entorhinal cortex	tissue	5.7
Temporal cortex	tissue	5.7
Putamen	tissue	5.6
Superior colliculi	tissue	5.6
Prefrontal cortex	tissue	5.5
Medulla oblongata	tissue	5.5
Thalamus	tissue	5.4
Occipital cortex	tissue	5.2
Motor cortex	tissue	4.9
Somatosensory cortex	tissue	4.6
Locus coeruleus	tissue	4.1
Nucleus accumbens	tissue	3.1
Heart muscle	tissue	3.0	low
Postcentral gyrus	tissue	3.0
Hippocampus	tissue	2.5	high
Choroid plexus	tissue	2.4
Vagina	tissue	1.9	not detected
Liver	tissue	1.7	medium
Ovary	tissue	1.5	medium
Placenta	tissue	1.5	high
Retina	tissue	0.8
Pancreas	tissue	0.8	high
Fallopian tube	tissue	0.8	low
Epididymis	tissue	0.7	medium
Cervix	tissue	0.6	low
Skin 1	tissue	0.6	not detected
Seminal vesicle	tissue	0.6	low
Endometrium 1	tissue	0.6	low
Frontal cortex	tissue	0.6
Caudate putamen	tissue	0.5
Adipose tissue	tissue	0.4	medium
Gallbladder	tissue	0.4	medium
Salivary gland	tissue	0.3	low
Colon	tissue	0.3	high
Spleen	tissue	0.3	low
Small intestine	tissue	0.3	high
Prostate	tissue	0.3	high
Adrenal gland	tissue	0.3	low
Testis	tissue	0.2	medium
Stomach 1	tissue	0.2	high
Esophagus	tissue	0.2	medium

Brain sub-regions (HPA Brain Atlas): detected in 292; highest nTPM — Dorsal hippocampus (19.8), Dorsal spinal cord (19.7), Lateral geniculate body (19.4), Frontal eye field (19.3), Lateral amygdala (18.7).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, ESRRA, FOXA2, FOXM1, FOXO1, HIF1A, HNF1A, HNF4A, KLF6, NEUROD1, NR0B2, NR1H2, NR1H3, NR5A2, ONECUT1, PAX6, PDX1, PPARG, PREB, RFX3, RXRA, SP1, SP3, SREBF1, STAT1, STAT5B, TFE3, USF1, USF2

miRNA regulators (miRDB)

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

showing 30 of 35 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6838-3P	98.40	65.88	559
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-6855-5P	97.51	66.03	830
HSA-MIR-4314	97.50	67.30	1369
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002

Functional genomics

gnomAD constraint: pLI 7.75e-07, LOEUF 0.866, missense Z 2.79 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000403799 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈5% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
7:44,145,139–44,152,363	379 / 536.2	0.71	no
7:44,152,364–44,153,313	4 / 29.7	0.13	yes (p 2.4e-06)
7:44,153,314–44,188,953	68 / 85.7	0.79	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• G-to-A polymorphism in the hepatic GCK promoter is associated with hepatic insulin resistance in normotensive Asian Indians with normal glucose tolerance. (PMID:11112984)
• These results are consistent with GKRP having one single binding site for phosphate esters. They also show that a missense mutation of GKRP can lead to a gain of function (PMID:11756407)
• Mutations are not a common cause of permanent neonatal diabetes in France. (PMID:11914755)
• mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. (PMID:12050210)
• insulin regulates both the association of GK with secretory granules and the activity of the enzyme within the pancreatic beta-cell. (PMID:12101177)
• Four novel GCK mutations, namely IVS2-7G>A, G72R, T206R and S263P, were identified in Canadian MODY patients. (PMID:12442280)
• Twenty different mutations in the HNF-4alpha, GCK and HNF-1alpha in 29 families. Three of 3, 10 of 11 and 1 of 6 of the mutations identified in HNF-4alpha, GCK and HNF-1alpha respectively, were new. (PMID:12627330)
• two novel spontaneous GCK-activating mutations whose clinical phenotype clearly differs from mutations in ATP-sensitive K(+) channel genes (PMID:12941786)
• summary of glucokinase mutations in glucose metabolism disorders. (PMID:14517946)
• Autosomal recessive inheritance and GLK deficiency are features typical for an inborn error of metabolism, which occurred in the glucose-insulin signaling pathway in these subjects. (PMID:14578306)
• fructose-2,6-diphosphate can stimulate hepatic glucokinase gene expression in an insulin-independent manner (PMID:14617577)
• high-fat feeding impairs both insulin- and exercise-stimulated muscle glucose uptake, but only exercise-stimulated MGU was corrected by HK II overexpression (PMID:14747279)
• We have found GLUT-2 and glucokinase mRNAs in several brain regions, including the ventromedial and arcuate nuclei of the hypothalamus (PMID:15009676)
• A G(-30)A polymorphism in the beta-cell-specific promoter of glucokinase (GK-30PM)increases the risk of CAD in individuals with and without type 2 diabetes mellitus. (PMID:15173029)
• Range of the clinical phenotype caused by GCK mutations varies from complete insulin deficiency to extreme hyperinsulinemia. (PMID:15277402)
• a mutation of the GCK gene was found in families and patients with maturity-onset diabetes of the young (PMID:15305805)
• Data describe the glucokinase V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. (PMID:15677479)
• COmmon genetic variation, in addition to rare mutations and environmental factors, can affect both fastinsg blood glucose and birth weight. (PMID:15677518)
• 5 novel mutations within the GCK gene, associated with Maturity-onset diabetes of the young, are discussed. (PMID:15841481)
• relative prevalence of 3% of MODY1 (two different mutations in two families), 10% of MODY2 (seven in eight), and 36% of MODY3 (21 in 28) among Danish kindred clinically diagnosed as MODY (PMID:15928245)
• Two new activating mutations of human glucokinase increase the affinity of the enzyme for glucose. (PMID:15987895)
• identification and functional characterization of missense mutations in the GCK gene in diabetic families that result in protein mutations Leu165–>Phe, Glu265–>Lys and Thr206–>Met. (PMID:16173921)
• glucokinase -30G>A polymorphism associates with elevated fasting and post-oral glucose tolerance test glycemia in the middle-aged whites as well as with impaired glucose regulation and WHO-defined metabolic syndrome (PMID:16186409)
• The prevalence of structural mutations in glucokinase gene responsible for early-onset diabetes appears to be rare among Chinese patients. (PMID:16331569)
• Families of young children with fasting hyperglycemia with family histories of diabetes showed mutations in glucokinase. (PMID:16444761)
• The -30G–>A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women. (PMID:16752173)
• The prevalence of mutations in the GSK gene was studied in Polish women with gestational diabetes. (PMID:16963153)
• The alteration in glucokinase (GK) activity caused by polymorphic activating mutations may have a more profound biological impact than the alleviation of inhibition caused by interaction with GKRP. (PMID:17082186)
• Different type 2 doabetes mutations impair glucokinase function through different mechanisms such as enzymatic activity, protein stability and increased interaction with the flucokinase receptor (PMID:17186219)
• GCK is associated with fetal growth and birth weight (PMID:17186458)
• Lack of genetic predisposition in offspring to progressive beta cell dysfunction in glucokinase mutation of mmothrs. (PMID:17216282)
• data support control of GK activity and Km through the ratio of distinct conformers (super-open, open, and closed) through either substrate or other ligand binding and/or dissociation (PMID:17260972)
• A study evaluating the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes is presented. (PMID:17327436)
• results suggest that cellular loss of GK catalytic activity rather than impaired translation or enhanced protein degradation may account for the hyperglycemia in subjects with V62M and G72R mutations (PMID:17389332)
• human glucokinase is allosterically activated by free polyubiquitin chains and its ubiquitin-dependent cotranslational proteasomal degradation (PMID:17561510)
• Almost 90% of the MODY cases in the group studied are explained by mutations in the major genes GCK (MODY2) and HNF-1alpha(MODY3), although differences in the relative prevalence of each form could be partly due to patient referral bias. (PMID:17573900)
• GCK is required for JNK and, unexpectedly, p38 activation by three bacterial PAMPs, lipopolysaccharide, peptidoglycan, and flagellin (PMID:17584736)
• Four missense mutations were found in the GCK gene. All mutations in the GCK gene co-segregated with diabetes mellitus. (PMID:17937063)
• study of a pedigree with 8 affected persistent hyperinsulinaemic hypoglycaemia of infancy individuals; the novel GCK mutation G68V is associated with variable phenotypic severity (PMID:17976205)
• adipocyte-derived Wnt signalling molecules regulate insulin secretion, glucokinase gene transcription and beta cell proliferation (PMID:17994217)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gck	ENSDARG00000068006
mus_musculus	Gck	ENSMUSG00000041798
rattus_norvegicus	Gck	ENSRNOG00000061527

Paralogs (4): HKDC1 (ENSG00000156510), HK1 (ENSG00000156515), HK2 (ENSG00000159399), HK3 (ENSG00000160883)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1270854) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 51 distinct phenotype terms.

Mouse phenotype (MP)	Records
hyperglycemia	16
impaired glucose tolerance	16
decreased circulating insulin level	5
decreased insulin secretion	4
increased circulating glucose level	4
postnatal lethality, complete penetrance	4
decreased body weight	3
increased urine glucose level	3
increased circulating insulin level	3
hepatic steatosis	3
abnormal pancreatic beta cell physiology	3
insulin resistance	3
decreased pancreatic beta cell mass	3
decreased liver glycogen level	3
hypoglycemia	2
postnatal growth retardation	2
abnormal glucose homeostasis	2
postnatal lethality	2
small pancreatic islets	2
decreased glucokinase activity	2
increased fasting circulating glucose level	2
abnormal circulating cholesterol level	1
increased body weight	1
increased circulating triglyceride level	1
increased circulating free fatty acids level	1

+26 more (showing top 25).

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Equus caballus	A2PYL6	100.0%	Diamond
Equus zebra	A2PYL7	100.0%	Diamond
Equus grevyi	A2PYL8	100.0%	Diamond
Pongo abelii	Q5RC71	99.2%	Diamond
Sus scrofa	Q1W674	96.1%	Diamond
Bos taurus	P27595	91.5%	Diamond
Nicotiana tabacum	Q9SEK2	85.7%	Diamond
Solanum tuberosum	Q9SQ76	85.7%	Diamond
Arabidopsis thaliana	P93834	85.2%	Diamond
Oryza sativa Japonica Group	Q5W676	82.8%	Diamond
Saccharomyces cerevisiae S288C	P04806	77.4%	Diamond
Schwanniomyces occidentalis	P50506	75.6%	Diamond
Candida albicans SC5314	P83776	75.6%	Diamond
Spinacia oleracea	Q9SEK3	74.5%	Diamond
Kluyveromyces lactis NRRL Y-1140	P33284	73.4%	Diamond
Aspergillus nidulans FGSC A4	P80581	57.4%	Diamond
Schizosaccharomyces pombe 972h-	Q09756	50.4%	Diamond
Schistosoma mansoni	Q26609	48.3%	Diamond
Drosophila melanogaster	Q9NFT7	45.3%	Diamond
Toxoplasma gondii	Q969A8	45.0%	Diamond
Aspergillus niger	Q92407	43.2%	Diamond
Brugia malayi	A0A0K0JFP3	41.6%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
MIR4649	ncRNA	100616346
AEBP1	protein-coding	165
POLD2	protein-coding	5425
MYL7	protein-coding	58498
YKT6	protein-coding	10652
CAMK2B	protein-coding	816
NUDCD3	protein-coding	23386

Protein

Protein identifiers

Hexokinase-4 — P35557 (reviewed: P35557)

Alternative names: Glucokinase, Hexokinase type IV, Hexokinase-D

All UniProt accessions (8): A0A5F9ZGW4, P35557, A0A5F9ZHE0, A0A8C8KJG0, A0A8C8PZE6, C9JQD1, H7BXV0, Q53Y25

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant. Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues. Since insulin secretion parallels glucose metabolism and the low glucose affinity of GCK ensures that it can change its enzymatic activity within the physiological range of glucose concentrations, GCK acts as a glucose sensor in the pancreatic beta cell. In pancreas, plays an important role in modulating insulin secretion. In liver, helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage. Required to provide D-glucose 6-phosphate for the synthesis of glycogen. Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate.

Subunit / interactions. Monomer. Interacts with MIDN; the interaction occurs preferentially at low glucose levels and results in inhibition of hexokinase activity. Interacts with GCKR; leading to sequestration in the nucleus.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion.

Disease relevance. Maturity-onset diabetes of the young 2 (MODY2) [MIM:125851] A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. The disease is caused by variants affecting the gene represented in this entry. Hyperinsulinemic hypoglycemia, familial, 3 (HHF3) [MIM:602485] A form of hyperinsulinemic hypoglycemia, a clinically and genetically heterogeneous disorder characterized by inappropriate insulin secretion from the pancreatic beta-cells in the presence of low blood glucose levels. HHF3 clinical features include loss of consciousness due to hypoglycemia, hypoglycemic coma, mental retardation due to repeated episodes of hypoglycemia, and seizures. HHF3 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility is associated with variants affecting the gene represented in this entry. Diabetes mellitus, permanent neonatal, 1 (PNDM1) [MIM:606176] An autosomal recessive form of permanent neonatal diabetes mellitus, a type of diabetes characterized by onset of persistent hyperglycemia within the first six months of life. Initial clinical manifestations include intrauterine growth retardation, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Subject to allosteric regulation. Low glucose and high fructose-6-phosphate triggers association with the inhibitor GCKR followed by sequestration in the nucleus.

Pathway. Carbohydrate metabolism; hexose metabolism. Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 1/4.

Similarity. Belongs to the hexokinase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P35557-1	1	yes
P35557-2	2
P35557-3	3

RefSeq proteins (5): NP_000153, NP_001341729, NP_001341732, NP_277042, NP_277043 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001312	Hexokinase	Family
IPR019807	Hexokinase_BS	Binding_site
IPR022672	Hexokinase_N	Domain
IPR022673	Hexokinase_C	Domain
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00349, PF03727

Enzyme classification (BRENDA)

• EC 2.7.1.1 — hexokinase (BRENDA: 77 organisms, 225 substrates, 336 inhibitors, 483 Km, 134 kcat entries)

Substrate kinetics (BRENDA)

21 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	—	184
D-GLUCOSE	0.003–45	112
D-FRUCTOSE	0.025–1510	46
D-MANNOSE	0.014–25.41	36
2-DEOXY-D-GLUCOSE	0.033–19.2	24
D-GLUCOSAMINE	0.06–2	12
UTP	0.288–30	7
ITP	1.9–16.6	6
CTP	0.52–5	5
GTP	0.231–0.788	4
N-ACETYL-D-GLUCOSAMINE	0.32–41.6	2
1,5-ANHYDRO-D-GLUCITOL	20	1
1-THIO-D-GLUCOSE	5	1
2-DEOXY-2-FLUORO-D-GLUCOSE	0.2	1
2-DEOXYGLUCOSE	18	1

Catalyzed reactions (Rhea)

• D-mannose + ATP = D-mannose 6-phosphate + ADP + H(+) (RHEA:11028)
• D-fructose + ATP = D-fructose 6-phosphate + ADP + H(+) (RHEA:16125)
• D-glucose + ATP = D-glucose 6-phosphate + ADP + H(+) (RHEA:17825)
• a D-hexose + ATP = a D-hexose 6-phosphate + ADP + H(+) (RHEA:22740)

UniProt features (188 total): sequence variant 118, helix 21, strand 19, binding site 11, mutagenesis site 9, turn 4, splice variant 2, region of interest 2, chain 1, domain 1

Structure

Experimental structures (PDB)

showing 30 of 35 structures by resolution:

PDB	Title	Method	Resolution (Å)
3F9M	Human pancreatic glucokinase in complex with glucose and activator showing a mobile flap	X-RAY DIFFRACTION	1.5
4NO7	Human Glucokinase in complex with a nanomolar activator.	X-RAY DIFFRACTION	1.7
4ISE	Human glucokinase in complex with novel activator …	X-RAY DIFFRACTION	1.78
4DCH	Insights into Glucokinase Activation Mechanism: Observation of Multiple Distinct Protein …	X-RAY DIFFRACTION	1.79
3VEV	Glucokinase in complex with an activator and glucose	X-RAY DIFFRACTION	1.8
3VF6	Glucokinase in complex with glucose and activator	X-RAY DIFFRACTION	1.86
6E0I	Crystal structure of Glucokinase in complex with compound 72	X-RAY DIFFRACTION	1.9
3IMX	Crystal Structure of human glucokinase in complex with a synthetic activator	X-RAY DIFFRACTION	2
4IXC	Crystal structure of Human Glucokinase in complex with a small molecule activator.	X-RAY DIFFRACTION	2
5V4X	Human glucokinase in complex with novel pyrazole activator.	X-RAY DIFFRACTION	2.08
4ISF	Human glucokinase in complex with novel activator …	X-RAY DIFFRACTION	2.09
4IWV	Crystals structure of Human Glucokinase in complex with small molecule activator	X-RAY DIFFRACTION	2.1
3H1V	Human glucokinase in complex with a synthetic activator	X-RAY DIFFRACTION	2.11
3IDH	Human pancreatic glucokinase in complex with glucose	X-RAY DIFFRACTION	2.14
3FGU	Catalytic complex of Human Glucokinase	X-RAY DIFFRACTION	2.15
3S41	Glucokinase in complex with activator and glucose	X-RAY DIFFRACTION	2.18
3A0I	Human glucokinase in complex with a synthetic activator	X-RAY DIFFRACTION	2.2
3QIC	The structure of human glucokinase E339K mutation	X-RAY DIFFRACTION	2.2
3VEY	glucokinase in complex with glucose and ATPgS	X-RAY DIFFRACTION	2.25
1V4S	Crystal structure of human glucokinase	X-RAY DIFFRACTION	2.3
4RCH	Discovery of 2-Pyridyl Ureas as Glucokinase Activators	X-RAY DIFFRACTION	2.3
4DHY	Crystal structure of human glucokinase in complex with glucose and activator	X-RAY DIFFRACTION	2.38
5V4W	Human glucokinase in complex with novel indazole activator.	X-RAY DIFFRACTION	2.39
3ID8	Ternary complex of human pancreatic glucokinase crystallized with activator, glucose and …	X-RAY DIFFRACTION	2.4
7T78	CRYSTAL STRUCTURE OF GLUCOKINASE (HEXOKINASE 4) COMPLEXED WITH LIGAND DIETHYL …	X-RAY DIFFRACTION	2.4
7T79	CRYSTAL STRUCTURE OF GLUCOKINASE (HEXOKINASE 4) COMPLEXED WITH LIGAND AKA DIETHYL …	X-RAY DIFFRACTION	2.4
3GOI	Human glucokinase in complex with a synthetic activator	X-RAY DIFFRACTION	2.52
4MLE	Human Glucokinase in Complex with Novel Amino Thiazole Activator	X-RAY DIFFRACTION	2.6
4ISG	Human glucokinase in complex with novel activator …	X-RAY DIFFRACTION	2.65
3FR0	Human glucokinase in complex with 2-amino benzamide activator	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35557-F1	93.87	0.85

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Other congenital disorders of metabolism, Diabetes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

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

Ligand- & substrate-binding residues (11)

Position	Role
256	substrate
290	substrate
295–296	ATP
332–336	ATP
411–415	ATP
78–83	ATP
151–152	substrate
168–169	substrate
204–205	substrate
228	ATP
231	substrate

Mutagenesis-validated functional residues (9)

Position	Phenotype
64	increased glucokinase activity based on measure of catalytic efficiency. increased affinity for glucose.
177	small change in glucokinase activity.
197	increased glucokinase activity based on measure of catalytic efficiency. increased affinity for glucose.
211	increased glucokinase activity based on measure of catalytic efficiency. increased affinity for glucose.
214	increased glucokinase activity based on measure of catalytic efficiency. increased affinity for glucose. no effect on affinity for atp.
215	increased glucokinase activity based on measure of catalytic efficiency. increased affinity for glucose. loss of inhibition by gckr. no …
256	inactive enzyme with no glucokinase activity.
414	small change in glucokinase activity.
453	increased glucokinase activity based on measure of catalytic efficiency. increased affinity for glucose.

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 18; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

18 pathways:

ID	Pathway	Evidence
R-HSA-5619073	Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) ⚕	curated
R-HSA-5619107	Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC) ⚕	curated
R-HSA-70171	Glycolysis	curated
R-HSA-170822	Regulation of Glucokinase by Glucokinase Regulatory Protein	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5619115	Disorders of transmembrane transporters ⚕	—
R-HSA-5619102	SLC transporter disorders ⚕	—
R-HSA-1266738	Developmental Biology	—
R-HSA-9614085	FOXO-mediated transcription	—
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	electronic
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-70326	Glucose metabolism	—
R-HSA-1430728	Metabolism	—
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-186712	Regulation of beta-cell development	—
R-HSA-210745	Regulation of gene expression in beta cells	electronic

MSigDB gene sets: 379 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, PID_HNF3B_PATHWAY, GOBP_NADPPLUS_METABOLIC_PROCESS, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_HORMONE_TRANSPORT, GOBP_CARBOHYDRATE_PHOSPHORYLATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS

GO Biological Process (23): intracellular glucose homeostasis (GO:0001678), glucose metabolic process (GO:0006006), glucose catabolic process (GO:0006007), glycolytic process (GO:0006096), regulation of glycolytic process (GO:0006110), response to glucose (GO:0009749), positive regulation of insulin secretion (GO:0032024), cellular response to insulin stimulus (GO:0032869), glucose homeostasis (GO:0042593), cellular response to leptin stimulus (GO:0044320), negative regulation of gluconeogenesis (GO:0045721), positive regulation of glycogen biosynthetic process (GO:0045725), regulation of insulin secretion (GO:0050796), glucose 6-phosphate metabolic process (GO:0051156), canonical glycolysis (GO:0061621), calcium ion import (GO:0070509), carbohydrate metabolic process (GO:0005975), purine nucleotide metabolic process (GO:0006163), hexose metabolic process (GO:0019318), organophosphate metabolic process (GO:0019637), nicotinamide nucleotide metabolic process (GO:0046496), carbohydrate phosphorylation (GO:0046835), carbohydrate derivative metabolic process (GO:1901135)

GO Molecular Function (13): glucokinase activity (GO:0004340), ATP binding (GO:0005524), D-glucose binding (GO:0005536), fructokinase activity (GO:0008865), mannokinase activity (GO:0019158), glucose sensor activity (GO:0141089), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), hexokinase activity (GO:0004396), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, alcohol group as acceptor (GO:0016773)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), cytosol (GO:0005829), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

13 top-level categories:

Category	Pathways
SLC transporter disorders	2
Glycolysis	1
Regulation of beta-cell development	1
Glucose metabolism	1
FOXO-mediated transcription	1
Developmental Biology	1
RNA Polymerase II Transcription	1
Disorders of transmembrane transporters	1
Disease	1
Metabolism of carbohydrates and carbohydrate derivatives	1
Metabolism	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

showing 60 of 77 GO namespaces:

Category	Terms
hexokinase activity	3
cellular anatomical structure	3
insulin secretion	2
transferase activity, transferring phosphorus-containing groups	2
cytoplasm	2
intracellular membrane-bounded organelle	2
glucose homeostasis	1
intracellular chemical homeostasis	1
hexose metabolic process	1
glucose metabolic process	1
hexose catabolic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase (phosphorylating, [NAD(P)+] ) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
glycolytic process	1
regulation of purine nucleotide catabolic process	1
regulation of generation of precursor metabolites and energy	1
regulation of carbohydrate catabolic process	1
regulation of ATP metabolic process	1
response to hexose	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
response to insulin	1
cellular response to peptide hormone stimulus	1
carbohydrate homeostasis	1
cellular response to hormone stimulus	1
response to leptin	1
gluconeogenesis	1
regulation of gluconeogenesis	1
negative regulation of biosynthetic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of small molecule metabolic process	1
glycogen biosynthetic process	1
regulation of glycogen biosynthetic process	1
positive regulation of macromolecule biosynthetic process	1
positive regulation of glycogen metabolic process	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
glucokinase activity	1
glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity	1
glucose catabolic process	1
glycolytic process through glucose-6-phosphate	1
calcium ion transport	1
primary metabolic process	1
nucleotide metabolic process	1
purine-containing compound metabolic process	1
monosaccharide metabolic process	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 41 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
glucose 6-phosphate metabolic process	BP	mutant phenotype
glucose catabolic process	BP	mutant phenotype
glucose homeostasis	BP	mutant phenotype
negative regulation of gluconeogenesis	BP	mutant phenotype
positive regulation of glycogen biosynthetic process	BP	mutant phenotype
positive regulation of insulin secretion	BP	mutant phenotype
regulation of insulin secretion	BP	mutant phenotype
cytosol	CC	direct assay
ATP binding	MF	direct assay
D-glucose binding	MF	direct assay
glucokinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,750 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCK	INS	P01308	939
GCK	SLC2A2	P11168	929
GCK	GCKR	Q14397	907
GCK	HNF1A	P20823	896
GCK	ABCC8	Q09428	869
GCK	G6PC2	Q9NQR9	863
GCK	MTNR1B	P49286	854
GCK	KCNJ11	Q14654	848
GCK	PDX1	P52945	841
GCK	ADPGK	Q9BRR6	828
GCK	GCG	P01275	809
GCK	G6PC3	Q9BUM1	808
GCK	G6PC1	P35575	800
GCK	KHK	P50053	800
GCK	INSR	P06213	791

IntAct

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

11 partners by confidence:

Partner	Interaction type	MIscore	Records
GCKR	physical association	0.720	5
SPDYE4	physical association	0.560	3
PFKFB1	direct interaction	0.560	2
SPOP	proximity	0.270	4
AKT1	proximity	0.270	1
BRAF	proximity	0.270	1
EGFR	proximity	0.270	1
FBXW7	proximity	0.270	1
PTEN	proximity	0.270	1
PTPN11	proximity	0.270	1
SMAD4	proximity	0.270	1

BioGRID (24 interactions; top human partners by supporting records): GCKR (Affinity Capture-Western; 6 records), AGL (Co-fractionation), CSF3R (Negative Genetic), GMIP (Co-fractionation), HK2 (Negative Genetic), ITGB7 (Negative Genetic), PARK2 (FRET), PCNA (Reconstituted Complex), PFKFB2 (Two-hybrid), PFKFB3 (PCA), PNMT (Positive Genetic), SMEK2 (Co-fractionation), SPDYE4 (Two-hybrid), UGP2 (Co-fractionation)

SIGNOR signaling

4 signaling interactions:

A	Effect	B	Mechanism
PDX1	“up-regulates quantity by expression”	GCK	“transcriptional regulation”
USF1	“up-regulates quantity by expression”	GCK	“transcriptional regulation”
GCK	“up-regulates quantity”	“alpha-D-glucose 6-phosphate(2-)”	“chemical modification”
GCK	“down-regulates quantity”	α-D-glucose	“chemical modification”

Disease & clinical

Genetic variants

Variant evidence for GCK: 1,416 ClinVar records (645 pathogenic / likely pathogenic); 489 ClinGen expert-panel interpretations; 47 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,416 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	344
Likely pathogenic	301
Uncertain significance	351
Likely benign	105
Benign	40

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 645 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
16134	NM_000162.5(GCK):c.683C>T (p.Thr228Met)	Pathogenic	reviewed by expert panel	21
36243	NM_000162.5(GCK):c.676G>A (p.Val226Met)	Pathogenic	reviewed by expert panel	16
129144	NM_000162.5(GCK):c.544G>A (p.Val182Met)	Pathogenic	reviewed by expert panel	15
426122	NM_000162.5(GCK):c.571C>T (p.Arg191Trp)	Pathogenic	reviewed by expert panel	15
431973	NM_000162.5(GCK):c.106C>T (p.Arg36Trp)	Pathogenic	reviewed by expert panel	14
36209	NM_000162.5(GCK):c.214G>A (p.Gly72Arg)	Pathogenic	reviewed by expert panel	13
211073	NM_000162.5(GCK):c.370G>A (p.Asp124Asn)	Pathogenic	reviewed by expert panel	13
393451	NM_000162.5(GCK):c.748C>T (p.Arg250Cys)	Pathogenic	reviewed by expert panel	13
393453	NM_000162.5(GCK):c.128G>A (p.Arg43His)	Pathogenic	reviewed by expert panel	13
585929	NM_000162.5(GCK):c.952G>A (p.Gly318Arg)	Pathogenic	reviewed by expert panel	13
804849	NM_000162.5(GCK):c.562G>A (p.Ala188Thr)	Pathogenic	reviewed by expert panel	13
36258	NM_000162.5(GCK):c.787T>C (p.Ser263Pro)	Pathogenic	reviewed by expert panel	12
447402	NM_000162.5(GCK):c.469G>A (p.Glu157Lys)	Pathogenic	reviewed by expert panel	12
585909	NM_000162.5(GCK):c.1174C>T (p.Arg392Cys)	Pathogenic	reviewed by expert panel	12
16135	NM_000162.5(GCK):c.781G>A (p.Gly261Arg)	Pathogenic	reviewed by expert panel	11

Per-variant reference — Sugi Variant

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

ClinGen expert-panel interpretations (489)

Expert ACMG interpretations from Monogenic Diabetes VCEP for maturity-onset diabetes of the young type 2; monogenic diabetes — a higher-authority tier than individual ClinVar submissions.

Assertion	Variants
Pathogenic	200
Likely Pathogenic	182
Uncertain Significance	95
Likely Benign	8
Benign	4

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 1,101):

Position(s)	Effect	Δscore	Sites
7:44145495–44145496	donor_loss	1.0000	5
7:44145740	acceptor_gain	1.0000
7:44146619	acceptor_loss	1.0000	2
7:44147834	acceptor_loss	1.0000
7:44150954–44150955	donor_loss	1.0000	3
7:44150960	donor_gain	1.0000
7:44152270	donor_loss	1.0000	2
7:44152426–44152427	acceptor_loss	1.0000	6
7:44145731–44145732	acceptor_loss	0.9900	6
7:44145735	acceptor_gain	0.9900

AlphaMissense

1,461 missense substitutions predicted likely pathogenic (of 3,085 scored), across 333 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M57	9	0.965	0.993
M210	9	0.886	0.992
M251	9	0.867	0.986
D205	8	0.999	1.000
D78	8	0.993	0.996
D274	8	0.988	0.996
F152	8	0.986	1.000
N231	8	0.984	0.999
D409	8	0.980	0.993
F123	8	0.975	0.998
F150	8	0.972	0.998
N204	8	0.968	0.999
F260	8	0.965	0.995
F316	8	0.964	0.989
H416	8	0.961	0.995
F171	8	0.957	0.999
F148	8	0.953	0.998
F419	8	0.948	0.995
F133	8	0.934	0.997
F84	8	0.931	0.992

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Liver Hepatocellular Carcinoma)

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	4.97e-05
Liver Hepatocellular Carcinoma (validation)	favorable	0.000134

Disease associations

OMIM: gene MIM:138079 | disease phenotypes: MIM:606176, MIM:125851, MIM:125850, MIM:606391, MIM:125853, MIM:602485, MIM:256450, MIM:600496, MIM:251260, MIM:300672, MIM:615715

GenCC curated gene-disease

8 curated gene-disease records:

Disease	Classification	Inheritance	Records
maturity-onset diabetes of the young type 2	Definitive	Autosomal dominant	4
hyperinsulinemic hypoglycemia, familial, 3	Definitive	Autosomal dominant	5
permanent neonatal diabetes mellitus 1	Strong	Autosomal recessive	4
transient neonatal diabetes mellitus	Strong	Autosomal recessive
diabetes mellitus, noninsulin-dependent	Strong	Autosomal dominant
type 2 diabetes mellitus	Strong	Autosomal dominant
maturity-onset diabetes of the young	Supportive	Autosomal dominant
permanent neonatal diabetes mellitus	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

2 validity classifications:

Disease	Classification	Inheritance
monogenic diabetes	Definitive	SD
hyperinsulinism due to glucokinase deficiency	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Congenital hyperinsulinism	green
Diabetes with additional phenotypes suggestive of a monogenic aetiology	green
Familial diabetes	green
Glucokinase-related fasting hyperglycaemia	green
Monogenic diabetes	green
Neonatal diabetes	green

Mondo (18): permanent neonatal diabetes mellitus 1 (MONDO:0100165), maturity-onset diabetes of the young type 2 (MONDO:0007453), monogenic diabetes (MONDO:0015967), maturity-onset diabetes of the young (MONDO:0018911), type 2 diabetes mellitus (MONDO:0005148), hyperinsulinemic hypoglycemia, familial, 3 (MONDO:0011236), gestational diabetes (MONDO:0005406), permanent neonatal diabetes mellitus (MONDO:0100164), hyperinsulinemic hypoglycemia, familial, 1 (MONDO:0009734), maturity-onset diabetes of the young type 3 (MONDO:0010894), familial hyperinsulinism (MONDO:0017182), diabetes mellitus (MONDO:0005015), Nijmegen breakage syndrome (MONDO:0009623), developmental and epileptic encephalopathy, 2 (MONDO:0010396), maturity-onset diabetes of the young type 1 (MONDO:0007452), pancytopenia-developmental delay syndrome (MONDO:0014317), transient neonatal diabetes mellitus (MONDO:0020525), (MONDO:0007455)

Orphanet (12): Rare genetic diabetes mellitus (Orphanet:183625), MODY (Orphanet:552), Congenital glucokinase-related hyperinsulinism (Orphanet:79299), Isolated permanent neonatal diabetes mellitus (Orphanet:99885), Autosomal dominant hyperinsulinism due to SUR1 deficiency (Orphanet:276575), Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency (Orphanet:276598), Familial hyperinsulinism (Orphanet:276525), Nijmegen breakage syndrome (Orphanet:647), Early infantile developmental and epileptic encephalopathy (Orphanet:1934), West syndrome (Orphanet:3451), CDKL5-deficiency disorder (Orphanet:505652), Pancytopenia-developmental delay syndrome (Orphanet:401764)

HPO phenotypes

showing 60 of 80 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000119	Abnormality of the genitourinary system
HP:0000124	Renal tubular dysfunction
HP:0000365	Hearing impairment
HP:0000488	Retinopathy
HP:0000819	Diabetes mellitus
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000855	Insulin resistance
HP:0000857	Neonatal insulin-dependent diabetes mellitus
HP:0000956	Acanthosis nigricans
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001324	Muscle weakness
HP:0001325	Hypoglycemic coma
HP:0001488	Bilateral ptosis
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001518	Small for gestational age
HP:0001520	Large for gestational age
HP:0001627	Abnormal heart morphology
HP:0001738	Exocrine pancreatic insufficiency
HP:0001824	Weight loss
HP:0001944	Dehydration
HP:0001952	Glucose intolerance
HP:0001953	Diabetic ketoacidosis
HP:0001985	Hypoketotic hypoglycemia
HP:0001988	Recurrent hypoglycemia
HP:0001998	Neonatal hypoglycemia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002123	Generalized myoclonic seizure
HP:0002173	Hypoglycemic seizures
HP:0002186	Apraxia
HP:0002270	Abnormality of the autonomic nervous system
HP:0002378	Hand tremor
HP:0002594	Pancreatic hypoplasia
HP:0002714	Downturned corners of mouth
HP:0002804	Arthrogryposis multiplex congenita
HP:0002919	Ketonuria
HP:0003074	Hyperglycemia
HP:0003076	Glycosuria
HP:0003477	Peripheral axonal neuropathy
HP:0003584	Late onset
HP:0003621	Juvenile onset
HP:0004904	Maturity-onset diabetes of the young
HP:0004924	Abnormal oral glucose tolerance
HP:0005487	Prominent metopic ridge
HP:0005750	Lower-limb joint contracture
HP:0005978	Type II diabetes mellitus
HP:0006274	Reduced pancreatic beta cells

GWAS associations

showing 30 of 47 associations:

Study	Trait	p-value
GCST000568_5	Fasting blood glucose	7e-92
GCST008362_201	Birth weight	4e-61
GCST001527_20	Fasting blood glucose (BMI interaction)	8e-56
GCST005186_5	Fasting blood glucose	6e-52
GCST007899_7	Fasting blood glucose	1e-50
GCST007954_30	Glycated hemoglobin levels	9e-38
GCST007954_31	Glycated hemoglobin levels	4e-35
GCST002586_9	Fasting plasma glucose	8e-27
GCST011587_11	Fasting blood glucose	8e-27
GCST005146_33	Birth weight	1e-26
GCST000276_3	Fasting plasma glucose	1e-25
GCST010661_7	Blood glucose levels	1e-25
GCST002390_11	Glycated hemoglobin levels	2e-22
GCST000803_3	Glycated hemoglobin levels	1e-20
GCST001233_18	Metabolite levels	2e-19
GCST010244_177	Triglyceride levels	3e-19
GCST001965_5	Glycemic traits	5e-18
GCST005180_4	Homeostasis model assessment of beta-cell function	2e-16
GCST006002_10	Blood sugar levels	7e-16
GCST007953_14	Glycated hemoglobin levels	9e-15
GCST007269_209	Pulse pressure	5e-14
GCST008363_59	Offspring birth weight	8e-14
GCST008363_60	Offspring birth weight	2e-13
GCST009379_294	Type 2 diabetes	2e-13
GCST001436_14	Metabolic syndrome	4e-13
GCST010173_68	Triglyceride levels	5e-13
GCST007847_44	Type 2 diabetes	5e-12
GCST000303_4	Glycated hemoglobin levels	6e-12
GCST008398_2	Glycated hemoglobin levels	3e-11
GCST006001_11	Hemoglobin A1c levels	4e-11

EFO canonical traits (from GWAS)

10 canonical traits:

EFO ID	Trait name
EFO:0004541	HbA1c measurement
EFO:0000195	metabolic syndrome
EFO:0004340	body mass index
EFO:0004344	birth weight
EFO:0004469	HOMA-B
EFO:0005939	parental genotype effect measurement
EFO:0004468	glucose measurement
EFO:0004530	triglyceride measurement
EFO:0005763	pulse pressure measurement
EFO:0009303	fructosamine measurement

MeSH disease descriptors

10 disease descriptors:

Descriptor	Name	Tree numbers
D003920	Diabetes Mellitus	C18.452.394.750; C19.246
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D016640	Diabetes, Gestational	C12.050.703.170; C18.452.394.750.448; C19.246.200
D049932	Nijmegen Breakage Syndrome	C18.452.284.600
C564064	CDKL5 deficiency disorder *(supp.)*
C563425	Diabetes Mellitus, Permanent Neonatal *(supp.)*
C538374	Hyperinsulinemic hypoglycemia, familial, 3 *(supp.)*
C562772	Mason-Type Diabetes *(supp.)*
C565101	Maturity-Onset Diabetes of the Young, Type 1 *(supp.)*
C563933	Maturity-Onset Diabetes of the Young, Type 3 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3820 (SINGLE PROTEIN), CHEMBL3885579 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

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

6 curated-mechanism drugs:

Drug	Modality	Max phase
DORZAGLIATIN	Small molecule	3
AZD-1656	Small molecule	2
LY-2608204	Small molecule	2
MK-0941	Small molecule	2
NERIGLIATIN	Small molecule	2
PF-04991532	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 711 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

5 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL3219124	AZD-1656	2	392
CHEMBL2165615	NERIGLIATIN	2	54
CHEMBL2165620	PF-04991532	2	51
CHEMBL3580737	MK-0941 FREE BASE	2	28
CHEMBL1783734	PIRAGLIATIN	2	186

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Hexokinases

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

Ligand	Action	Affinity	Parameter
AZD1656	Activation	7.24	pEC50

Binding affinities (BindingDB)

971 measured of 1047 human assays (1079 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL4067028	EC50	0.8 nM
CHEMBL4086771	EC50	1 nM
(7R)-7-[5-[(3-chloro-1,7-naphthyridin-8-yl)amino]-2-fluorophenyl]-7-methyl-5,5-dioxo-5lambda6-thia-8-azaspiro[3.5]non-8-en-9-amine	IC50	1.15 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
CHEMBL4086782	EC50	1.4 nM
methyl 3-[6-[5-(4-ethylsulfonylphenoxy)-6-(1-methyl-5-oxopyrrolidin-2-yl)-1H-indol-2-yl]-3-pyridinyl]propanoate	EC50	1.9 nM	US-9453038: Glucokinase activator compounds, compositions containing such compounds, and methods of treatment
CHEMBL3113985	IC50	2 nM
methyl 3-[4-[[6-(1-methyl-5-oxopyrrolidin-2-yl)-2-pyrazin-2-yl-1H-indol-5-yl]oxy]phenyl]propanoate	EC50	2.1 nM	US-9453038: Glucokinase activator compounds, compositions containing such compounds, and methods of treatment
CHEMBL4104680	EC50	3.4 nM
5-[3-[(3R)-5-amino-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-3-yl]-4,5-difluoroanilino]-1H-pyrido[3,4-b]pyrazin-2-one	IC50	3.7 nM	US-9556135: Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
CHEMBL3114185	IC50	4 nM
methyl 3-[4-[[6-(1-methyl-5-oxopyrrolidin-2-yl)-2-pyridin-2-yl-1H-indol-5-yl]oxy]phenyl]propanoate	EC50	4.3 nM	US-9453038: Glucokinase activator compounds, compositions containing such compounds, and methods of treatment
CHEMBL4067037	EC50	4.8 nM
CHEMBL3235148	EC50	5 nM
CHEMBL3319529	IC50	5 nM
CHEMBL3319540	IC50	5 nM
CHEMBL3319534	IC50	5 nM
2-[5-chloro-2-[[3-(4-methoxyphenyl)sulfanyl-6-pyridin-2-ylsulfanylpyridine-2-carbonyl]amino]-1,3-thiazol-4-yl]acetic acid	EC50	5.7 nM	US-9527838: 2-pyridinecarboxamide derivatives, compositions containing such compounds, and methods of treatment
CHEMBL3319544	IC50	6 nM
CHEMBL3577727	EC50	6 nM
CHEMBL3577728	EC50	6 nM
CHEMBL3577729	EC50	6 nM
CHEMBL3577715	EC50	6 nM
CHEMBL3577735	EC50	6 nM
CHEMBL3114186	IC50	6 nM
CHEMBL3114183	IC50	6 nM
ethyl 2-[[2-[[3-(3,4-dichlorophenyl)sulfanyl-6-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carbonyl]amino]-1,3-thiazol-5-yl]sulfanyl]acetate	EC50	6.2 nM	US-9527838: 2-pyridinecarboxamide derivatives, compositions containing such compounds, and methods of treatment
Staurosporine, 8	IC50	6.5 nM
CHEMBL3319542	IC50	7 nM
CHEMBL3319541	IC50	7 nM
CHEMBL3577736	EC50	7 nM
CHEMBL3113980	IC50	7 nM
ethyl 2-[[2-[[3-(4-methoxyphenyl)sulfanyl-6-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carbonyl]amino]-1,3-thiazol-5-yl]sulfanyl]acetate	EC50	7.5 nM	US-9527838: 2-pyridinecarboxamide derivatives, compositions containing such compounds, and methods of treatment
ethyl 2-[5-chloro-2-[[3-(3,4-dichlorophenyl)sulfanyl-6-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carbonyl]amino]-1,3-thiazol-4-yl]acetate	EC50	7.6 nM	US-9527838: 2-pyridinecarboxamide derivatives, compositions containing such compounds, and methods of treatment
ethyl 2-[5-chloro-2-[[3-(4-fluorophenyl)sulfanyl-6-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carbonyl]amino]-1,3-thiazol-4-yl]acetate	EC50	8 nM	US-9527838: 2-pyridinecarboxamide derivatives, compositions containing such compounds, and methods of treatment
CHEMBL3235155	EC50	8 nM
CHEMBL3319543	IC50	8 nM
methyl 3-[2-[6-(1-methyl-5-oxopyrrolidin-2-yl)-5-(4-methylsulfonylphenoxy)-1H-indol-2-yl]-1,3-thiazol-5-yl]propanoate	EC50	8.9 nM	US-9453038: Glucokinase activator compounds, compositions containing such compounds, and methods of treatment
CHEMBL3577732	EC50	9 nM
CHEMBL3114187	IC50	9 nM
2-[5-chloro-2-[[3-(4-fluorophenyl)sulfanyl-6-pyridin-2-ylsulfanylpyridine-2-carbonyl]amino]-1,3-thiazol-4-yl]acetic acid	EC50	9.6 nM	US-9527838: 2-pyridinecarboxamide derivatives, compositions containing such compounds, and methods of treatment
3-methyl-2-(4-(1-methyl-1H-pyrazol-3-ylamino)quinazolin-6-yloxy)benzonitrile	EC50	10 nM
CHEMBL4793665	IC50	10 nM
3-(4-methoxyphenyl)sulfanyl-N-[5-[2-(methylamino)-2-oxoethyl]sulfanyl-1,3-thiazol-2-yl]-6-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carboxamide	EC50	10.8 nM	US-9527838: 2-pyridinecarboxamide derivatives, compositions containing such compounds, and methods of treatment
CHEMBL3319551	IC50	11 nM
CHEMBL3317472	IC50	11 nM
methyl 3-[4-[[6-(1-methyl-5-oxopyrrolidin-2-yl)-2-[5-(trifluoromethyl)-2-pyridinyl]-1H-indol-5-yl]oxy]phenyl]propanoate	EC50	11.4 nM	US-9453038: Glucokinase activator compounds, compositions containing such compounds, and methods of treatment
CHEMBL3577720	EC50	12 nM
CHEMBL3764079	EC50	12 nM
ethyl 2-[[2-[[3-(4-fluorophenyl)sulfanyl-6-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]pyridine-2-carbonyl]amino]-1,3-thiazol-5-yl]sulfanyl]acetate	EC50	13.4 nM	US-9527838: 2-pyridinecarboxamide derivatives, compositions containing such compounds, and methods of treatment
methyl 3-[6-[6-(1-acetylpyrrolidin-2-yl)-5-[[6-(azetidine-1-carbonyl)-3-pyridinyl]oxy]-1H-indol-2-yl]-3-pyridinyl]propanoate	EC50	13.9 nM	US-9453038: Glucokinase activator compounds, compositions containing such compounds, and methods of treatment

ChEMBL bioactivities

1393 potent at pChembl≥5 of 1426 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.31	IC50	0.488	nM	STAUROSPORINE
9.10	EC50	0.8	nM	CHEMBL4067028
9.09	IC50	0.81	nM	STAUROSPORINE
9.00	IC50	1	nM	CHEMBL3319533
9.00	EC50	1	nM	CHEMBL4086771
8.85	EC50	1.4	nM	CHEMBL4086782
8.72	EC50	1.9	nM	CHEMBL3918883
8.70	IC50	2	nM	CHEMBL3113985
8.70	EC50	2	nM	CHEMBL4086782
8.68	EC50	2.1	nM	CHEMBL3893442
8.68	EC50	2.1	nM	CHEMBL4068048
8.67	Kd	2.16	nM	CHEMBL3217925
8.62	Kd	2.42	nM	CHEMBL3580738
8.62	EC50	2.4	nM	CHEMBL4067028
8.62	EC50	2.4	nM	CHEMBL4083339
8.53	Kd	2.93	nM	MK-0941 FREE BASE
8.47	EC50	3.4	nM	CHEMBL4104680
8.43	EC50	3.7	nM	CHEMBL4067028
8.42	EC50	3.8	nM	CHEMBL3901777
8.42	EC50	3.8	nM	CHEMBL4086771
8.40	IC50	4	nM	CHEMBL3114185
8.38	EC50	4.2	nM	CHEMBL4078915
8.38	EC50	4.2	nM	CHEMBL4067028
8.37	EC50	4.3	nM	CHEMBL3969091
8.35	EC50	4.5	nM	CHEMBL4078915
8.35	EC50	4.5	nM	CHEMBL4086771
8.32	EC50	4.8	nM	CHEMBL4067037
8.32	EC50	4.8	nM	CHEMBL4068048
8.30	EC50	5	nM	CHEMBL3235148
8.30	IC50	5	nM	CHEMBL3319529
8.30	IC50	5	nM	CHEMBL3319549
8.30	IC50	5	nM	CHEMBL3319540
8.30	IC50	5	nM	CHEMBL3319534
8.26	EC50	5.5	nM	CHEMBL4086771
8.24	EC50	5.7	nM	CHEMBL4092800
8.22	IC50	6	nM	CHEMBL3114186
8.22	IC50	6	nM	CHEMBL3114183
8.22	IC50	6	nM	CHEMBL3319544
8.22	IC50	6	nM	CHEMBL3578107
8.22	EC50	6	nM	CHEMBL3577715
8.22	EC50	6	nM	CHEMBL3577727
8.22	EC50	6	nM	CHEMBL3577728
8.22	EC50	6	nM	CHEMBL3577729
8.22	EC50	6	nM	CHEMBL3577735
8.15	IC50	7	nM	CHEMBL3113980
8.15	IC50	7	nM	CHEMBL3319542
8.15	IC50	7	nM	CHEMBL3319541
8.15	IC50	7	nM	CHEMBL3578087
8.15	EC50	7	nM	CHEMBL3577736
8.10	EC50	8	nM	CHEMBL3235155

PubChem BioAssay actives

1145 with measured affinity, of 2891 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
(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	1715336: Inhibition of human GCK using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0005	uM
1-methyl-5-[5-[(6-methylsulfonyl-3-pyridinyl)oxy]-2-[5-(trifluoromethyl)-2-pyridinyl]-1H-indol-6-yl]pyrrolidin-2-one	1446944: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0008	uM
1-methyl-5-[5-[(6-methylsulfonyl-3-pyridinyl)oxy]-2-pyridin-2-yl-1H-indol-6-yl]pyrrolidin-2-one	1446944: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0008	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(1-methylpyrazol-4-yl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0010	uM
1-methyl-5-[5-[(6-methylsulfonyl-3-pyridinyl)oxy]-2-(5-methyl-1,3-thiazol-2-yl)-1H-indol-6-yl]pyrrolidin-2-one	1446944: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0010	uM
5-[5-(4-ethylsulfonylphenoxy)-2-[5-(trifluoromethyl)-2-pyridinyl]-1H-indol-6-yl]-1-methylpyrrolidin-2-one	1446944: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0014	uM
1,1,1-trifluoro-2-[4-[(2S)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)-4-thiophen-2-ylsulfonylpiperazin-1-yl]phenyl]propan-2-ol	1068881: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by Alpha Screen assay	ic50	0.0020	uM
5-[2-[5-(2-hydroxypropan-2-yl)-2-pyridinyl]-5-[(6-methylsulfonyl-3-pyridinyl)oxy]-1H-indol-6-yl]-1-methylpyrrolidin-2-one	1446944: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0021	uM
methyl 6-[6-(1-methyl-5-oxopyrrolidin-2-yl)-5-[(6-methylsulfonyl-3-pyridinyl)oxy]-1H-indol-2-yl]pyridine-3-carboxylate	1446944: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0034	uM
2-[4-[(2S)-4-[(6-amino-3-pyridinyl)sulfonyl]-2-prop-1-ynylpiperazin-1-yl]phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1068881: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by Alpha Screen assay	ic50	0.0040	uM
1-methyl-5-[5-[(6-methylsulfonyl-3-pyridinyl)oxy]-2-pyrazin-2-yl-1H-indol-6-yl]pyrrolidin-2-one	1446944: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0042	uM
ethyl 4-[[6-(1-methyl-5-oxopyrrolidin-2-yl)-2-[5-(trifluoromethyl)-2-pyridinyl]-1H-indol-5-yl]oxy]benzoate	1446942: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 2.5 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0048	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(3-methoxyprop-1-ynyl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0050	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(1-ethylpyrazol-4-yl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0050	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(4-methylthiophen-2-yl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0050	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-pyridin-3-yl-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0050	uM
N-[4-[2-(ethylamino)-2-oxoethyl]-1,3-thiazol-2-yl]-3-(3-methyl-2-pyridinyl)-5-(4-methylsulfonylphenoxy)benzamide	1129057: Activation of recombinant human pancreatic glucokinase using 10 mM glucose by spectrophotometry	ec50	0.0050	uM
2-[5-chloro-2-[[3-(4-methoxyphenyl)sulfanyl-6-pyridin-2-ylsulfanylpyridine-2-carbonyl]amino]-1,3-thiazol-4-yl]acetic acid	1446979: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0057	uM
2-[2-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-3-pyridinyl]phenol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0060	uM
3-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)-5-[2-[3-(2-pyrrolidin-1-ylethylamino)phenyl]ethynyl]benzamide	1226037: Activation of recombinant human pancreatic glucokinase using 10 mM glucose as substrate by G6PDH coupled assay	ec50	0.0060	uM
3-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)-5-[2-[3-(2-piperidin-1-ylethylamino)phenyl]ethynyl]benzamide	1226037: Activation of recombinant human pancreatic glucokinase using 10 mM glucose as substrate by G6PDH coupled assay	ec50	0.0060	uM
3-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)-5-[2-[3-(2-pyrrolidin-1-ylethoxy)phenyl]ethynyl]benzamide	1226037: Activation of recombinant human pancreatic glucokinase using 10 mM glucose as substrate by G6PDH coupled assay	ec50	0.0060	uM
(2R)-2-[4-[5-[(6-amino-3-pyridinyl)sulfonyl]-1,3-thiazol-2-yl]-3-chlorophenyl]propane-1,2-diol	1226494: Inhibition of human biotin-labeled GKRP and fluorescein-labeled human GK interaction preincubated for 20 mins prior to fluorescein-labeled human GK addition measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0060	uM
(2S)-2-[4-[(2S)-4-[(6-amino-3-pyridinyl)sulfonyl]-2-prop-1-ynylpiperazin-1-yl]phenyl]-1,1,1-trifluoropropan-2-ol	1068881: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by Alpha Screen assay	ic50	0.0060	uM
2-[4-[4-[(6-amino-3-pyridinyl)sulfonyl]-2-prop-1-ynylpiperazin-1-yl]phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1068881: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by Alpha Screen assay	ic50	0.0060	uM
3-[2-[3-[2-(dimethylamino)ethylamino]phenyl]ethynyl]-5-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)benzamide	1226037: Activation of recombinant human pancreatic glucokinase using 10 mM glucose as substrate by G6PDH coupled assay	ec50	0.0060	uM
3-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)-5-[3-(oxan-2-yloxy)prop-1-ynyl]benzamide	1226037: Activation of recombinant human pancreatic glucokinase using 10 mM glucose as substrate by G6PDH coupled assay	ec50	0.0060	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-phenyl-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0070	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(2-fluorophenyl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0070	uM
3-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)-5-[2-[3-(2-piperidin-1-ylethoxy)phenyl]ethynyl]benzamide	1226037: Activation of recombinant human pancreatic glucokinase using 10 mM glucose as substrate by G6PDH coupled assay	ec50	0.0070	uM
2-[6-[6-[(6-amino-3-pyridinyl)sulfonyl]-2-anilino-3-pyridinyl]-3-pyridinyl]-1,1,1-trifluoropropan-2-ol	1226494: Inhibition of human biotin-labeled GKRP and fluorescein-labeled human GK interaction preincubated for 20 mins prior to fluorescein-labeled human GK addition measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0070	uM
1,1,1-trifluoro-2-[4-[(2S)-2-[[(3S)-3-methylmorpholin-4-yl]methyl]-4-thiophen-2-ylsulfonylpiperazin-1-yl]phenyl]propan-2-ol	1068881: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by Alpha Screen assay	ic50	0.0070	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(3-fluorophenyl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0080	uM
N-[4-[(1-methoxypropan-2-ylamino)methyl]-1,3-thiazol-2-yl]-3-(3-methyl-2-pyridinyl)-5-(4-methylsulfonylphenoxy)benzamide	1129057: Activation of recombinant human pancreatic glucokinase using 10 mM glucose by spectrophotometry	ec50	0.0080	uM
3-[(2S)-1-methoxypropan-2-yl]oxy-5-[2-[3-[2-(2-methylimidazol-1-yl)ethylamino]phenyl]ethynyl]-N-(1-methylpyrazol-3-yl)benzamide	1226037: Activation of recombinant human pancreatic glucokinase using 10 mM glucose as substrate by G6PDH coupled assay	ec50	0.0090	uM
(2R)-2-[4-[(2S)-4-[(6-amino-3-pyridinyl)sulfonyl]-2-prop-1-ynylpiperazin-1-yl]phenyl]-1,1,1-trifluoropropan-2-ol	1068881: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by Alpha Screen assay	ic50	0.0090	uM
1-[4-[5-[(5-pyridin-2-ylsulfanyl-3-quinolin-5-yloxy-2-pyridinyl)amino]-1,2,4-thiadiazol-3-yl]piperidin-1-yl]ethanone	1653850: Activation of glucokinase (unknown origin)	ec50	0.0093	uM
4-[[6-(1-methyl-5-oxopyrrolidin-2-yl)-2-[5-(trifluoromethyl)-2-pyridinyl]-1H-indol-5-yl]oxy]benzoic acid	1446944: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0096	uM
2-[5-chloro-2-[[3-(4-fluorophenyl)sulfanyl-6-pyridin-2-ylsulfanylpyridine-2-carbonyl]amino]-1,3-thiazol-4-yl]acetic acid	1446979: Activation of recombinant human glucokinase assessed as conversion of D-glucose to D-glucose-6-phosphate in presence of 10 mM glucose by G6PDH coupled spectrophotometric assay	ec50	0.0096	uM
2-[4-[5-[(6-amino-3-pyridinyl)sulfonyl]-1,3-thiazol-2-yl]-3-chlorophenyl]propane-1,2-diol	1226494: Inhibition of human biotin-labeled GKRP and fluorescein-labeled human GK interaction preincubated for 20 mins prior to fluorescein-labeled human GK addition measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0100	uM
3-methyl-2-[4-[(1-methylpyrazol-3-yl)amino]quinazolin-6-yl]oxybenzonitrile	437790: Activation of N-terminal His-tagged human recombinant liver glucokinase expressed in Escherichia coli BL21 (DE3) by glucose-6-phosphate dehydrogenase coupled continuous spectrophotometric assay in presence of 10 mM glucose	ec50	0.0100	uM
5-[2-(1-ethylpiperidin-4-yl)-1,3-thiazol-5-yl]-3-(pyridin-4-ylmethoxy)pyridin-2-amine	1679420: Inhibition of human GCK using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0102	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(4-fluorophenyl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0110	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(5-fluoro-3-pyridinyl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0110	uM
3-[2-(1H-indol-5-yl)ethynyl]-5-[(2S)-1-methoxypropan-2-yl]oxy-N-(1-methylpyrazol-3-yl)benzamide	1226037: Activation of recombinant human pancreatic glucokinase using 10 mM glucose as substrate by G6PDH coupled assay	ec50	0.0120	uM
2-[(Z)-1-(3-chloro-4-methylsulfonylphenyl)-2-cyclopentylethenyl]-1H-pyrrolo[2,3-b]pyridine	1276628: Activation of recombinant human glucokinase assessed as NADPH formation using glucose as substrate incubated for 30 mins in presence of NADP+ and glucose 6-phosphate dehydrogenase	ec50	0.0124	uM
2-[6-[4-[(6-amino-3-pyridinyl)sulfonyl]piperazin-1-yl]-5-(3-hydroxyprop-1-ynyl)-3-pyridinyl]-1,1,1,3,3,3-hexafluoropropan-2-ol	1182398: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP compound incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by AlphaScreen assay	ic50	0.0140	uM
1-[5-(cyclohexylmethyl)-3-[(2-ethyl-3-pyridinyl)oxy]-2-pyridinyl]-3-methylurea	1176538: Activation of human recombinant Glucokinase measured over 5 mins by G6-PD coupled assay in presence of 5 mM glucose	ec50	0.0140	uM
1-[4-(2,6-difluorophenoxy)-5-(6-ethoxy-3-pyridinyl)-2-pyridinyl]-3-methylurea	1627607: Activation of human recombinant glucokinase using 5 mM glucose monitored over 5 mins in presence of NAD+ by glucose 6-phosphate dehydrogenase coupled assay	ec50	0.0140	uM
(1R,5R,6R)-8-[[(2S)-4-thiophen-2-ylsulfonyl-1-[4-[(2R)-1,1,1-trifluoro-2-hydroxypropan-2-yl]phenyl]piperazin-2-yl]methyl]-3-oxa-8-azabicyclo[3.2.1]octan-6-ol	1068881: Inhibition of fluorescein-labeled human GK interaction with biotin-labeled human GKRP incubated for 20 mins prior to addition of fluorescein-labeled GK measured after 2 to 4 hrs by Alpha Screen assay	ic50	0.0140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases methylation, decreases expression, affects cotreatment	2
mono-(2-ethylhexyl)phthalate	affects expression, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, affects cotreatment, affects expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	2
benzo(b)fluoranthene	affects cotreatment, affects expression	1
bisphenol A	decreases expression	1
fluoranthene	affects cotreatment, affects expression	1
1,2,5,6-dibenzanthracene	affects expression, affects cotreatment	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
benazol P	affects expression	1
benzamide	increases activity	1
1-methylphenanthrene	affects cotreatment, affects expression	1
dibenzo(a,l)pyrene	affects expression, affects cotreatment	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
fenugreek seed meal	affects expression	1
tetraarsenic tetrasulfide	affects cotreatment, decreases expression	1
bisphenol S	decreases expression	1
6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide	decreases reaction, increases expression, increases reaction	1
Imatinib Mesylate	affects cotreatment, decreases expression	1
Atorvastatin	decreases expression, increases reaction	1
Resveratrol	increases reaction, decreases reaction, increases expression	1
Arsenic Trioxide	decreases reaction, affects binding	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	increases methylation	1
Estradiol	increases expression	1
Folic Acid	decreases expression	1
Metformin	decreases activity, decreases reaction, decreases expression	1
Rifampin	decreases expression, increases reaction	1

ChEMBL screening assays

228 unique, capped per target: 226 binding, 1 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1032034	Binding	Activation of flag-tagged human recombinant liver glucokinase expressed in Escherichia coli by glucose-6-phosphate dehydrogenase coupled continuous spectrophotometric assay in presence of 2.5 mM glucose	Structure-activity relationships of 3,5-disubstituted benzamides as glucokinase activators with potent in vivo efficacy. — *Bioorg Med Chem*
CHEMBL4813785	ADMET	Inhibition of human hexokinase-4 at 20 uM relative to control	Synthesis, biochemical, and biological evaluation of C2 linkage derivatives of amino sugars, inhibitors of glucokinase from Trypanosoma cruzi. — *Bioorg Med Chem Lett*
CHEMBL865109	Functional	Activation of glucokinase	Design of a potent, soluble glucokinase activator with excellent in vivo efficacy. — *Bioorg Med Chem Lett*

Cellosaurus cell lines

9 cell lines: 5 induced pluripotent stem cell, 2 spontaneously immortalized cell line, 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A4NV	QBRIi010-A	Induced pluripotent stem cell	Male
CVCL_A4NW	QBRIi011-A	Induced pluripotent stem cell	Male
CVCL_A4NX	QBRIi010-B	Induced pluripotent stem cell	Male
CVCL_A4NY	QBRIi010-C	Induced pluripotent stem cell	Male
CVCL_AJ80	GM13532	Transformed cell line	Female
CVCL_C9JN	SDQLCHi063-A	Induced pluripotent stem cell	Male
CVCL_HA58	BHK-PPI-C16-GCK	Spontaneously immortalized cell line	Male
CVCL_HA59	BHK-PPI-C16-GCK-GLUT	Spontaneously immortalized cell line	Male
CVCL_HA63	Melligen	Cancer cell line	Male

Clinical trials (associated diseases)

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

showing 60 of 321 trials:

NCT	Phase	Status	Title
NCT02624817	Phase 4	COMPLETED	Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes
NCT02624830	Phase 4	UNKNOWN	Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR)
NCT00006163	Phase 4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	Phase 4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	Phase 4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	Phase 4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	Phase 4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	Phase 4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	Phase 4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	Phase 4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	Phase 4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	Phase 4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	Phase 4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	Phase 4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	Phase 4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	Phase 4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	Phase 4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	Phase 4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	Phase 4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	Phase 4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	Phase 4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	Phase 4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	Phase 4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	Phase 4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	Phase 4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	Phase 4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	Phase 4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	Phase 4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	Phase 4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	Phase 4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	Phase 4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	Phase 4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	Phase 4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	Phase 4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	Phase 4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	Phase 4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	Phase 4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	Phase 4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	Phase 4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	Phase 4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	Phase 4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	Phase 4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus
NCT00241605	Phase 4	COMPLETED	AVANDAMET Versus Metformin For Type 2 Diabetes Mellitus
NCT00254085	Phase 4	UNKNOWN	Substitution of First Phase Insulin Response in Patient With Type 2 Diabetes.
NCT00258804	Phase 4	COMPLETED	Insulin Glargine During and After the Period of Fasting in Ramadan
NCT00262548	Phase 4	COMPLETED	C-Reactive Protein (CRP) in Obese Diabetic Women
NCT00264589	Phase 4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00264901	Phase 4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00265746	Phase 4	WITHDRAWN	Prevention of Diabetes Mellitus Development in Women Who Had Already Experienced A Gestational Diabetes
NCT00268645	Phase 4	COMPLETED	Insulin Glargine in Type 2 Diabetes
NCT00272077	Phase 4	COMPLETED	Insulin Glargine in Type 2 Diabetes Mellitus
NCT00272831	Phase 4	COMPLETED	The Use of Cilostazol in Patients With Diabetic Nephropathy
NCT00274274	Phase 4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00279201	Phase 4	COMPLETED	The DURABLE Trial: Evaluating the Durability of Starter Insulin Regimens in Patients With Type 2 Diabetes (IOOV)
NCT00282360	Phase 4	COMPLETED	Effect of Metabolic Therapy in Patients With Chronic Ischemic Heart Disease
NCT00282451	Phase 4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes
NCT00283049	Phase 4	TERMINATED	Insulin Glargine Injection Treatment in Place of Thiazolidinedione (TZD), Sulfonylurea, or Metformin in Triple Agent Therapy for Type 2 Diabetes Mellitus (T2DM) Adult Subjects With Unsatisfactory Control
NCT00283777	Phase 4	COMPLETED	Chromium and Insulin Action
NCT00290394	Phase 4	COMPLETED	Ambulatory Blood Pressure Reduction After Rosiglitazone Treatment In Normotensive Type 2 Diabetic Patients
NCT00296296	Phase 4	COMPLETED	Immunosuppression Impact on the Metabolic Control of Kidney Transplant With Pre-Existing Type 2 Diabetes (DM)

Predicted chemistry — Sugi Predict

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