Target Information

Target General Infomation
Target ID
T87166
Former ID
TTDC00141
Target Name
Glucokinase
Gene Name
GCK
Synonyms
HK IV; HK4; Hexokinase D; Hexokinase type IV; GCK
Target Type
Clinical Trial
Disease Diabetes [ICD9: 253.5, 588.1; ICD10: E23.2, N25.1]
Non-insulin dependent diabetes [ICD10: E11.9]
Obesity; Diabetes [ICD9: 250, 278; ICD10: E08-E13, E66]
Type 2 diabetes [ICD9: 250; ICD10: E11]
Unspecified [ICD code not available]
Function
Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting asan insulin-sensitive determinant of hepatic glucose usage.
BioChemical Class
Kinase
Target Validation
T87166
UniProt ID
P35557
EC Number
EC 2.7.1.2
Sequence
MLDDRARMEAAKKEKVEQILAEFQLQEEDLKKVMRRMQKEMDRGLRLETHEEASVKMLPT
YVRSTPEGSEVGDFLSLDLGGTNFRVMLVKVGEGEEGQWSVKTKHQMYSIPEDAMTGTAE
MLFDYISECISDFLDKHQMKHKKLPLGFTFSFPVRHEDIDKGILLNWTKGFKASGAEGNN
VVGLLRDAIKRRGDFEMDVVAMVNDTVATMISCYYEDHQCEVGMIVGTGCNACYMEEMQN
VELVEGDEGRMCVNTEWGAFGDSGELDEFLLEYDRLVDESSANPGQQLYEKLIGGKYMGE
LVRLVLLRLVDENLLFHGEASEQLRTRGAFETRFVSQVESDTGDRKQIYNILSTLGLRPS
TTDCDIVRRACESVSTRAAHMCSAGLAGVINRMRESRSEDVMRITVGVDGSVYKLHPSFK
ERFHASVRRLTPSCEITFIESEEGSGRGAALVSAVACKKACMLGQ
Drugs and Mode of Action
Drug(s) AMG 151 Drug Info Phase 2 Type 2 diabetes [523678]
AZD1656 Drug Info Phase 2 Diabetes [523091], [542677]
GK1-399 Drug Info Phase 2 Diabetes [525135]
LY-2599506 Drug Info Phase 2 Diabetes [522877]
LY-2608204 Drug Info Phase 2 Type 2 diabetes [523573]
PF-04937319 Drug Info Phase 2 Type 2 diabetes [523774]
PF-04991532 Drug Info Phase 2 Diabetes [523436]
ADV-1002401 Drug Info Phase 1 Type 2 diabetes [549053]
AZD5658 Drug Info Phase 1 Obesity; Diabetes [550290]
BMS-820132 Drug Info Phase 1 Type 2 diabetes [523348]
DS-7309 Drug Info Phase 1 Diabetes [524456]
TAK-329 Drug Info Phase 1 Diabetes [523386]
TTP-547 Drug Info Phase 1 Diabetes [551801]
ZYGK-1 Drug Info Phase 1 Diabetes [523690]
AZD6370 Drug Info Discontinued in Phase 2 Type 2 diabetes [548122]
TTP-355 Drug Info Discontinued in Phase 2 Diabetes [548396]
AZD-6714 Drug Info Discontinued in Phase 1 Type 2 diabetes [522643]
Inhibitor ADV-1002401 Drug Info [544410]
AMG 151 Drug Info [551195]
Beta-D-Glucose Drug Info [551393]
BMS-820132 Drug Info [533272]
DS-7309 Drug Info [551209]
GK1-399 Drug Info [550110]
LY-2599506 Drug Info [551195]
TAK-329 Drug Info [551984]
Stimulator AZD-6714 Drug Info [551194]
Activator AZD1656 Drug Info [550288]
AZD5658 Drug Info [550290]
AZD6370 Drug Info [550288]
GKA-23 Drug Info [543714]
GKA1 Drug Info [535916]
LY-2608204 Drug Info [551101]
PF-04991532 Drug Info [532788], [533022]
PSN-101 Drug Info [550543]
SKL-19014 Drug Info [543714]
TTP-355 Drug Info [548397]
TTP-547 Drug Info [543714]
ZYGK-1 Drug Info [543714]
Modulator PF-04937319 Drug Info [533212]
Piragliatin Drug Info
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Glycolysis / Gluconeogenesis
Galactose metabolism
Starch and sucrose metabolism
Amino sugar and nucleotide sugar metabolism
Butirosin and neomycin biosynthesis
Metabolic pathways
Biosynthesis of antibiotics
Carbon metabolism
Insulin signaling pathway
Insulin secretion
Prolactin signaling pathway
Glucagon signaling pathway
Type II diabetes mellitus
Maturity onset diabetes of the young
Central carbon metabolism in cancer
Pathway Interaction Database FOXA2 and FOXA3 transcription factor networks
HIF-1-alpha transcription factor network
PathWhiz Pathway Nucleotide Sugars Metabolism
Starch and Sucrose Metabolism
Galactose Metabolism
Trehalose Degradation
Reactome Regulation of gene expression in beta cells
Glucose transport
Glycolysis
WikiPathways SIDS Susceptibility Pathways
Glycolysis and Gluconeogenesis
MAPK Signaling Pathway
Regulation of beta-cell development
Metabolism of carbohydrates
Hexose transport
References
Ref 522643ClinicalTrials.gov (NCT00886366) Single Ascending Dose Study With Healthy Male Volunteers and Type II Diabetic Patients. U.S. National Institutes of Health.
Ref 522877ClinicalTrials.gov (NCT01024244) A Study of LY2599506 in Patients With Type 2 Diabetes. U.S. National Institutes of Health.
Ref 523091ClinicalTrials.gov (NCT01152385) Japan Dose Regimen Study of AZD1656 in Japanese Type 2 Diabetes Mellitus Patients. U.S. National Institutes of Health.
Ref 523348ClinicalTrials.gov (NCT01290575) Multiple Ascending Dose Study of BMS-820132 in Patients With Type 2 Diabetes. U.S. National Institutes of Health.
Ref 523386ClinicalTrials.gov (NCT01311076) TAK-329 Glucose Clamp Study. U.S. National Institutes of Health.
Ref 523436ClinicalTrials.gov (NCT01338870) Study of Safety and Efficacy of PF-04991532 in Subjects With Type 2 Diabetes. U.S. National Institutes of Health.
Ref 523573ClinicalTrials.gov (NCT01408095) A Study in Patients With Type 2 Diabetes. U.S. National Institutes of Health.
Ref 523678ClinicalTrials.gov (NCT01464437) AMG 151 Amgen Protocol Number 20100761. U.S. National Institutes of Health.
Ref 523690ClinicalTrials.gov (NCT01472809) A Clinical Study to Evaluate Safety, Tolerability and Pharmacokinetics of Oral ZYGK1 in Healthy Volunteers. U.S. National Institutes of Health.
Ref 523774ClinicalTrials.gov (NCT01517373) Study To Understand Efficacy And Safety Of Investigational Agent (PF-04937319) Compared To Approved Agent (Glimepiride) In Patients With Diabetes On Metformin. U.S. National Institutes of Health.
Ref 524456ClinicalTrials.gov (NCT01956305) Randomized, Placebo-controlled, 2 Period, Single-blind, Sequential, Multiple Ascending Dose Study. U.S. National Institutes of Health.
Ref 525135ClinicalTrials.gov (NCT02405260) Add Glucokinase Activator to Target A1c. U.S. National Institutes of Health.
Ref 542677(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7701).
Ref 548122Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022135)
Ref 548396Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025266)
Ref 549053Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031821)
Ref 550290Clinical pipeline report, company report or official report of AstraZeneca (2011).
Ref 551801New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches. Rob M. Jones, David E. Thurston, David Rotella, Salvatore Guccione, Ana Martinez. Page(92).
Ref 532788The hepatoselective glucokinase activator PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats. PLoS One. 2014 May 23;9(5):e97139.
Ref 533022Comparison of the circulating metabolite profile of PF-04991532, a hepatoselective glucokinase activator, across preclinical species and humans: potential implications in metabolites in safety testing assessment. Drug Metab Dispos. 2015 Feb;43(2):190-8.
Ref 533212Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes. Diabetes Obes Metab. 2015 Aug;17(8):751-9.
Ref 533272Utilization of the Zucker Diabetic Fatty (ZDF) Rat Model for Investigating Hypoglycemia-related Toxicities. Toxicol Pathol. 2015 Aug;43(6):825-37.
Ref 535916Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators. Diabetes. 2004 Mar;53(3):535-41.
Ref 543714(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2798).
Ref 544410The Hepatoselective Glucokinase Activator PF-04991532 Ameliorates Hyperglycemia without Causing Hepatic Steatosis in Diabetic Rats. PLoS One. 2014; 9(5): e97139.
Ref 548397Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025266)
Ref 550110Clinical pipeline report, company report or official report of vTv Therapeutics, NCT02405260.
Ref 550288Clinical pipeline report, company report or official report of AstraZeneca (2009).
Ref 550290Clinical pipeline report, company report or official report of AstraZeneca (2011).
Ref 550543CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.
Ref 551101Clinical pipeline report, company report or official report of Eli Lilly.
Ref 551194Glucokinase (GCK). SciBX 2(37); doi:10.1038/scibx.2009.1408. Sep. 24 2009
Ref 551195This week in therapeutics Endocrine disease. SciBX 2(37); doi:10.1038/scibx.2009.1408. Sept. 24, 2009
Ref 551209Glucokinase alternative. SciBX 6(45); doi:10.1038/scibx.2013.1279. Nov. 21 2013
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 551984Clinical pipeline report, company report or official report of Takeda.

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