Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTDLNGZ)

• DTT Name: Glucokinase (GCK)
• Synonyms: Hexokinase type IV; Hexokinase D; HK4; HK IV
• Gene Name: GCK
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: HXK4_HUMAN
• TTD ID: T87166
• EC Number: EC 2.7.1.2
• Sequence:
  MLDDRARMEAAKKEKVEQILAEFQLQEEDLKKVMRRMQKEMDRGLRLETHEEASVKMLPT
  YVRSTPEGSEVGDFLSLDLGGTNFRVMLVKVGEGEEGQWSVKTKHQMYSIPEDAMTGTAE
  MLFDYISECISDFLDKHQMKHKKLPLGFTFSFPVRHEDIDKGILLNWTKGFKASGAEGNN
  VVGLLRDAIKRRGDFEMDVVAMVNDTVATMISCYYEDHQCEVGMIVGTGCNACYMEEMQN
  VELVEGDEGRMCVNTEWGAFGDSGELDEFLLEYDRLVDESSANPGQQLYEKLIGGKYMGE
  LVRLVLLRLVDENLLFHGEASEQLRTRGAFETRFVSQVESDTGDRKQIYNILSTLGLRPS
  TTDCDIVRRACESVSTRAAHMCSAGLAGVINRMRESRSEDVMRITVGVDGSVYKLHPSFK
  ERFHASVRRLTPSCEITFIESEEGSGRGAALVSAVACKKACMLGQ
• 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.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Galactose metabolism (hsa00052)
  Starch and sucrose metabolism (hsa00500)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Butirosin and neomycin biosynthesis (hsa00524)
  Metabolic pathways (hsa01100)
  Biosynthesis of antibiotics (hsa01130)
  Carbon metabolism (hsa01200)
  Insulin signaling pathway (hsa04910)
  Insulin secretion (hsa04911)
  Prolactin signaling pathway (hsa04917)
  Glucagon signaling pathway (hsa04922)
  Type II diabetes mellitus (hsa04930)
  Maturity onset diabetes of the young (hsa04950)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Glucose transport (R-HSA-70153)
  Glycolysis (R-HSA-70171)
  Regulation of gene expression in beta cells (R-HSA-210745)
• BioCyc Pathway: MetaCyc:HS02935-MON

Molecular Interaction Atlas (MIA) of This DTT

16 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMG 151	DMGOFL3	Type-2 diabetes	5A11	Phase 2	[2]
AZD1656	DMUE90I	Diabetic complication	5A2Y	Phase 2	[1]
GK1-399	DMLFSMX	Diabetic complication	5A2Y	Phase 2	[3]
LY-2599506	DMMI0RH	Diabetic complication	5A2Y	Phase 2	[2]
LY-2608204	DM4EF9Y	Type-2 diabetes	5A11	Phase 2	[4]
PF-04937319	DMQMF4O	Type-2 diabetes	5A11	Phase 2	[5]
PF-04991532	DM94NBE	Diabetic complication	5A2Y	Phase 2	[6]
TTP399	DMBKQSZ	Type 2 diabetes	5A11	Phase 2	[7]
ADV-1002401	DMHIPF5	Type-2 diabetes	5A11	Phase 1	[8]
AZD5658	DMV6DF3	Diabetic complication	5A2Y	Phase 1	[9]
BMS-820132	DMCX0H7	Type-2 diabetes	5A11	Phase 1	[10]
DS-7309	DM7C4U9	Diabetic complication	5A2Y	Phase 1	[11]
HMS5552	DMRYM03	Type-2 diabetes	5A11	Phase 1	[12]
TAK-329	DMMWNQP	Diabetic complication	5A2Y	Phase 1	[13]
TTP-547	DMYFUOP	Diabetic complication	5A2Y	Phase 1	[14]
ZYGK-1	DM4IG16	Diabetic complication	5A2Y	Phase 1	[14]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD6370	DMVZSRG	Type-2 diabetes	5A11	Discontinued in Phase 2	[1]
TTP-355	DMCEGN4	Diabetic complication	5A2Y	Discontinued in Phase 2	[15]
AZD-6714	DMHV3IW	Type-2 diabetes	5A11	Discontinued in Phase 1	[16]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Beta-D-Glucose	DM5IHYP	Discovery agent	N.A.	Investigative	[17]
GKA-23	DMIENSW	Diabetic complication	5A2Y	Investigative	[14]
GKA1	DM9P62Y	Discovery agent	N.A.	Investigative	[18]
Piragliatin	DMOE39X	Discovery agent	N.A.	Investigative	[19]
PSN-101	DMUROIY	Diabetic complication	5A2Y	Investigative	[20]
SKL-19014	DM5T4Y1	Non-insulin dependent diabetes	5A11	Investigative	[14]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	2.72E-01	0.76	0.52

References

• [1] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [2] This week in therapeutics Endocrine disease. SciBX 2(37); doi:10.1038/scibx.2009.1408. Sept. 24, 2009
• [3] Clinical pipeline report, company report or official report of vTv Therapeutics, NCT02405260.
• [4] Clinical pipeline report, company report or official report of Eli Lilly.
• [5] Two 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.
• [6] The hepatoselective glucokinase activator PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats. PLoS One. 2014 May 23;9(5):e97139.
• [7] Clinical pipeline report, company report or official report of vTv Therapeutics.
• [8] The Hepatoselective Glucokinase Activator PF-04991532 Ameliorates Hyperglycemia without Causing Hepatic Steatosis in Diabetic Rats. PLoS One. 2014; 9(5): e97139.
• [9] Clinical pipeline report, company report or official report of AstraZeneca (2011).
• [10] Utilization of the Zucker Diabetic Fatty (ZDF) Rat Model for Investigating Hypoglycemia-related Toxicities. Toxicol Pathol. 2015 Aug;43(6):825-37.
• [11] Glucokinase alternative. SciBX 6(45); doi:10.1038/scibx.2013.1279. Nov. 21 2013
• [12] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [13] Clinical pipeline report, company report or official report of Takeda.
• [14] URL: 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).
• [15] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025266)
• [16] Glucokinase (GCK). SciBX 2(37); doi:10.1038/scibx.2009.1408. Sep. 24 2009
• [17] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [18] Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators. Diabetes. 2004 Mar;53(3):535-41.
• [19] Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study.J Clin Endocrinol Metab.2010 Nov;95(11):5028-36.
• [20] CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008.