Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Gastric H(+)/K(+) ATPase (Proton pump)
• Synonyms: Proton pump; Potassium-transporting ATPase
• Gene Name: ATP4A
• DTT Type: Successful target; [1]
• UniProt ID: ATP4A_HUMAN ; ATP4B_HUMAN
• TTD ID: T92687
• Sequence:
  MGKAENYELYSVELGPGPGGDMAAKMSKKKKAGGGGGKRKEKLENMKKEMEINDHQLSVA
  ELEQKYQTSATKGLSASLAAELLLRDGPNALRPPRGTPEYVKFARQLAGGLQCLMWVAAA
  ICLIAFAIQASEGDLTTDDNLYLAIALIAVVVVTGCFGYYQEFKSTNIIASFKNLVPQQA
  TVIRDGDKFQINADQLVVGDLVEMKGGDRVPADIRILAAQGCKVDNSSLTGESEPQTRSP
  ECTHESPLETRNIAFFSTMCLEGTVQGLVVNTGDRTIIGRIASLASGVENEKTPIAIEIE
  HFVDIIAGLAILFGATFFIVAMCIGYTFLRAMVFFMAIVVAYVPEGLLATVTVCLSLTAK
  RLASKNCVVKNLEAVETLGSTSVICSDKTGTLTQNRMTVSHLWFDNHIHTADTTEDQSGQ
  TFDQSSETWRALCRVLTLCNRAAFKSGQDAVPVPKRIVIGDASETALLKFSELTLGNAMG
  YRDRFPKVCEIPFNSTNKFQLSIHTLEDPRDPRHLLVMKGAPERVLERCSSILIKGQELP
  LDEQWREAFQTAYLSLGGLGERVLGFCQLYLNEKDYPPGYAFDVEAMNFPSSGLCFAGLV
  SMIDPPRATVPDAVLKCRTAGIRVIMVTGDHPITAKAIAASVGIISEGSETVEDIAARLR
  VPVDQVNRKDARACVINGMQLKDMDPSELVEALRTHPEMVFARTSPQQKLVIVESCQRLG
  AIVAVTGDGVNDSPALKKADIGVAMGIAGSDAAKNAADMILLDDNFASIVTGVEQGRLIF
  DNLKKSIAYTLTKNIPELTPYLIYITVSVPLPLGCITILFIELCTDIFPSVSLAYEKAES
  DIMHLRPRNPKRDRLVNEPLAAYSYFQIGAIQSFAGFTDYFTAMAQEGWFPLLCVGLRAQ
  WEDHHLQDLQDSYGQEWTFGQRLYQQYTCYTVFFISIEVCQIADVLIRKTRRLSAFQQGF
  FRNKILVIAIVFQVCIGCFLCYCPGMPNIFNFMPIRFQWWLVPLPYGILIFVYDEIRKLG
  VRCCPGSWWDQELYY
• Function: Proton pump of the stomach. Exchanges potassium from the intestinal lumen with cytoplasmic hydronium and is the enzyme primarily responsible for the acidification of the stomach contents and the activation of the digestive enzyme pepsin.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Collecting duct acid secretion (hsa04966)
  Gastric acid secretion (hsa04971)
• Reactome Pathway: Ion transport by P-type ATPases (R-HSA-936837)
• BioCyc Pathway: MetaCyc:HS02790-MON

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dexlansoprazole	DM1DBV5	Erosive esophagitis	DA25.0	Approved	[1]
Esomeprazole	DM7BN0X	Cystic fibrosis	CA25	Approved	[1]
Omeprazole	DM471KJ	Cystic fibrosis	CA25	Approved	[1]
Pantoprazole	DMSVOCZ	Gastrinoma	2C10.1	Approved	[1]
Vonoprazan	DMO6315	Helicobacter infection	DA42-DA63	Approved	[2]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RQ-00000004	DM9T8OF	Gastroesophageal reflux disease	DA22.Z	Phase 3	[3]
AZD-0865	DMM0N1F	Gastrointestinal disease	DE2Z	Phase 2	[4]
S-tenatoprazole	DMJ1DIB	Peptic ulcer	DA61	Phase 2	[5]
YH-4808	DMCHFB0	Duodenal ulcer	DA63	Phase 2	[6]

10 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LEMINOPRAZOLE	DMBKNJT	Ulcerative colitis	DD71	Discontinued in Preregistration	[7]
PUMAPRAZOLE	DMB069L	Duodenal ulcer	DA63	Discontinued in Phase 3	[8]
SKF-96067	DMXW1Y3	Peptic ulcer	DA61	Discontinued in Phase 3	[9]
AR-H047108	DMBTG8J	Duodenal ulcer	DA63	Discontinued in Phase 2	[10]
SORAPRAZAN	DMCS8FM	Peptic ulcer	DA61	Discontinued in Phase 2	[11]
TY-11345	DMQWA2R	Peptic ulcer	DA61	Discontinued in Phase 2	[12]
CS-526	DMXKB8V	Gastroesophageal reflux disease	DA22.Z	Discontinued in Phase 1	[13]
SKF-97574	DM1XEUV	Peptic ulcer	DA61	Discontinued in Phase 1	[9]
Saviprazole	DM79E6W	Peptic ulcer	DA61	Terminated	[14]
SK&F-95601	DMRM7H0	Peptic ulcer	DA61	Terminated	[15]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
YH-1238	DM6FEMV	Discovery agent	N.A.	Investigative	[16]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2008
• [3] N-(2-hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), a novel, potent, and selective acid pump antagonist for the treatment of gastroesophageal reflux disease. J Pharmacol Exp Ther. 2009 Feb;328(2):671-9.
• [4] Mechanism of action of AZD0865, a K+-competitive inhibitor of gastric H+,K+-ATPase. Biochem Pharmacol. 2007 Jan 15;73(2):198-205.
• [5] Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in heal... Aliment Pharmacol Ther. 2004 Mar 15;19(6):655-62.
• [6] Poor effectiveness of proton pump inhibitors in non-erosive reflux disease: the truth in the end! Neurogastroenterol Motil.2012 Aug;24(8):697-704.
• [7] Vasoinhibitory effect of leminoprazole, a H+,K(+)-ATPase inhibitor, on rat aortic rings. Gen Pharmacol. 1996 Jan;27(1):117-21.
• [8] Effects of pumaprazole (BY841), a novel reversible proton pump antagonist, and of omeprazole, on intragastric acidity before and after cure of Heli... Aliment Pharmacol Ther. 1999 Jan;13(1):27-34.
• [9] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [10] Early stellate cell activation and veno-occlusive-disease (VOD)-like hepatotoxicity in dogs treated with AR-H047108, an imidazopyridine proton pump inhibitor.Toxicol Pathol.2008 Jul;36(5):727-37.
• [11] Soraprazan: setting new standards in inhibition of gastric acid secretion.J Pharmacol Exp Ther.2007 Jun;321(3):866-74.
• [12] Biochemical and pharmacological properties of a newly synthesized proton pump (H+/K(+)-ATPase) inhibitor, TY-11345 in experimental animals. Jpn J Pharmacol. 1993 Aug;62(4):363-71.
• [13] Pharmacological profile of novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methyl cyclopropyl]methyl}-1H-pyrrolo[2,3-d]... J Pharmacol Exp Ther. 2007 Oct;323(1):308-17.
• [14] Gastric acid inhibitory profile of saviprazole (HOE 731) compared to omeprazole. Pharmacology. 1991;43(6):293-303.
• [15] 2-[[(4-Amino-2-pyridyl)methyl]sulfinyl]benzimidazole H+/K+-ATPase inhibitors.The relationship between pyridine basicity, stability, and activity.J Med Chem.1989 Aug;32(8):1970-7.
• [16] Compositions for improving gastrointestinal nutrient and drug absorption