Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4QPUL)

• DTT Name: Antithrombin-III (ATIII)
• Synonyms: SERPINC1; ATIII; AT3
• Gene Name: SERPINC1
• DTT Type: Successful target; [1]
• BioChemical Class: Serpin protein
• UniProt ID: ANT3_HUMAN
• TTD ID: T73476
• Sequence:
  MYSNVIGTVTSGKRKVYLLSLLLIGFWDCVTCHGSPVDICTAKPRDIPMNPMCIYRSPEK
  KATEDEGSEQKIPEATNRRVWELSKANSRFATTFYQHLADSKNDNDNIFLSPLSISTAFA
  MTKLGACNDTLQQLMEVFKFDTISEKTSDQIHFFFAKLNCRLYRKANKSSKLVSANRLFG
  DKSLTFNETYQDISELVYGAKLQPLDFKENAEQSRAAINKWVSNKTEGRITDVIPSEAIN
  ELTVLVLVNTIYFKGLWKSKFSPENTRKELFYKADGESCSASMMYQEGKFRYRRVAEGTQ
  VLELPFKGDDITMVLILPKPEKSLAKVEKELTPEVLQEWLDELEEMMLVVHMPRFRIEDG
  FSLKEQLQDMGLVDLFSPEKSKLPGIVAEGRDDLYVSDAFHKAFLEVNEEGSEAAASTAV
  VIAGRSLNPNRVTFKANRPFLVFIREVPLNTIIFMGRVANPCVK
• Function: Most important serine protease inhibitorin plasma that regulates the blood coagulation cascade. At-iii inhibits thrombin as well as factors ixa, xa and xia. Its inhibitory activity is greatly enhanced in the presence of heparin.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ardeparin	DMYRX8B	Deep vein thrombosis	BD71	Approved	[2]
Heparin Calcium	DMEVXY6	Coagulation defect	3B10.0	Approved	[2]
Heparin Sodium	DM9KHZL	Coagulation defect	3B10.0	Approved	[3]
Sulodexide	DMNUC42	Tinnitus	MC41	Approved	[4]

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Heparin low molecular weight	DMGFULM	Thrombosis	DB61-GB90	Phase 3	[5]
KW-3357	DMP3GI2	Coagulation defect	3B10.0	Phase 3	[6]
Unfractionated heparin	DMCWM03	Thrombosis	DB61-GB90	Phase 3	[7]
M118	DML0I2Z	Acute coronary syndrome	BA41	Phase 2	[8]
O-desulfated heparin	DMJL4A7	Chronic obstructive pulmonary disease	CA22	Phase 2	[9]
PMX-60056	DMWT73D	Coagulation defect	3B10.0	Phase 2	[10]
MER-102	DME18UM	Thrombosis	DB61-GB90	Phase 1	[11]
OPK-0018	DMLUYAJ	Asthma	CA23	Phase 1	[3]
RO-14	DM95F8B	Phlebothrombosis	GB90.3	Phase 1	[12]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Deligoparin sodium	DMXKWAL	Ulcerative colitis	DD71	Discontinued in Phase 3	[3]

6 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alpha-D-Mannose	DMF5DLW	Discovery agent	N.A.	Investigative	[13]
Heparin Pentasaccharide	DMY16VG	Discovery agent	N.A.	Investigative	[13]
LHD-4	DMKI70D	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]
N-Formylmethionine	DM7GBDX	Discovery agent	N.A.	Investigative	[13]
Org-36764	DM4SFKW	Discovery agent	N.A.	Investigative	[14]
PNU-87663	DM6SZVE	Discovery agent	N.A.	Investigative	[15]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Chronic obstructive pulmonary disease	CA23	Lung tissue	2.83E-02	0.04	0.35
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	4.05E-01	0.02	0.14
Asthma	CA23	Nasal and bronchial airway	9.48E-01	1.50E-03	6.15E-03

References

• [1] Oral heparin: status review. Thromb J. 2006; 4: 6.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] 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: 2632).
• [4] Review of pharmacodynamics, pharmacokinetics, and therapeutic properties of sulodexide. Med Res Rev. 1998 Jan;18(1):1-20.
• [5] Effects of low molecular weight heparin on a severely antithrombin III-decreased disseminated intravascular coagulation model in rabbits. Thromb Res. 1995 Dec 1;80(5):391-8.
• [6] Company report (kyowa-kirin)
• [7] Heparin with low affinity to antithrombin III inhibits the activation of prothrombin in normal plasma. Thromb Res. 1982 Nov 15;28(4):487-97.
• [8] Clinical pipeline report, company report or official report of Momentapharma.
• [9] Structural determinants of the capacity of heparin to inhibit the formation of the human amplification C3 convertase. J Clin Invest. 1981 Jan;67(1):223-8.
• [10] Parenteral Anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Correction in: Chest. 2013 August; 144(2): 721.
• [11] Clinical pipeline report, company report or official report of Merrion's GIPET technology.
• [12] Pharmacological effects and clinical applications of ultra low molecular weight heparins. Drug Discov Ther. 2014 Feb;8(1):1-10.
• [13] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [14] Pre-clinical pharmacological profile of the novel glycoconjugate Org 36764 with both factor Xa and thrombin (IIa) inhibitory activities. Thromb Haemost. 2000 Oct;84(4):611-20.
• [15] List of drugs in development for neurodegenerative diseases.Update June 2004.Neurodegener Dis.2004;1(2-3):113-52.