Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZHA0O)

• DTT Name: Carbonic anhydrase IV (CA-IV)
• Synonyms: Carbonic anhydrase 4; Carbonate dehydratase IV; CAIV
• Gene Name: CA4
• DTT Type: Successful target; [1]
• BioChemical Class: Alpha-carbonic anhydrase
• UniProt ID: CAH4_HUMAN
• TTD ID: T53378
• EC Number: EC 4.2.1.1
• Sequence:
  MRMLLALLALSAARPSASAESHWCYEVQAESSNYPCLVPVKWGGNCQKDRQSPINIVTTK
  AKVDKKLGRFFFSGYDKKQTWTVQNNGHSVMMLLENKASISGGGLPAPYQAKQLHLHWSD
  LPYKGSEHSLDGEHFAMEMHIVHEKEKGTSRNVKEAQDPEDEIAVLAFLVEAGTQVNEGF
  QPLVEALSNIPKPEMSTTMAESSLLDLLPKEEKLRHYFRYLGSLTTPTCDEKVVWTVFRE
  PIQLHREQILAFSQKLYYDKEQTVSMKDNVRPLQQLGQRTVIKSGAPGRPLPWALPALLG
  PMLACLLAGFLR
• Function: May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid. Reversible hydration of carbon dioxide.
• KEGG Pathway:
  Nitrogen metabolism (hsa00910)
  Proximal tubule bicarbonate reclamation (hsa04964)
• Reactome Pathway:
  Erythrocytes take up oxygen and release carbon dioxide (R-HSA-1247673)
  Reversible hydration of carbon dioxide (R-HSA-1475029)
  Erythrocytes take up carbon dioxide and release oxygen (R-HSA-1237044)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Brinzolamide	DMBAPFG	Ocular hypertension	9C61.01	Approved	[2]
Salicyclic acid	DM2F8XZ	Acne vulgaris	ED80	Approved	[3]
Sulfamylon	DMIO1K0	Bacterial infection	1A00-1C4Z	Approved	[1]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Curcumin	DMQPH29	Solid tumour/cancer	2A00-2F9Z	Phase 3	[4]
PARABEN	DMEW5Z8	N. A.	N. A.	Phase 3	[5]
PHENOL	DM1QSM3	N. A.	N. A.	Phase 2/3	[4]
Coumate	DMVKW0N	Breast cancer	2C60-2C65	Phase 2	[6]
Sodium pyruvate	DMST6A3	Asthma	CA23	Phase 1/2	[7]
SULFAMIDE	DMMAS3K	N. A.	N. A.	Phase 1	[8]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FERULIC ACID	DMJC7NF	Discovery agent	N.A.	Patented	[5]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SPERMINE	DMD4BFY	N. A.	N. A.	Terminated	[9]

60 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-(3,4-dichlorophenyl)-3-hydroxyurea	DMVOJ7K	Discovery agent	N.A.	Investigative	[10]
2,4-Disulfamyltrifluoromethylaniline	DM2AW0Z	Discovery agent	N.A.	Investigative	[1]
2-oxo-2H-chromene-3-carboxylic acid	DMFN769	Discovery agent	N.A.	Investigative	[11]
2-Propyl-pentanoic acid 4-sulfamoyl-benzyl ester	DM1L7PN	Discovery agent	N.A.	Investigative	[12]
2-Propyl-pentanoic acid 4-sulfamoyl-benzylamide	DMVWUME	Discovery agent	N.A.	Investigative	[12]
3-Amino-benzenesulfonamide	DME0TNA	Discovery agent	N.A.	Investigative	[1]
4-(2-AMINOETHYL)BENZENESULFONAMIDE	DMEK6WX	Discovery agent	N.A.	Investigative	[1]
4-Amino-3-bromo-benzenesulfonamide	DMVUCZK	Discovery agent	N.A.	Investigative	[1]
4-Amino-3-chloro-benzenesulfonamide	DMERTQ4	Discovery agent	N.A.	Investigative	[1]
4-Amino-3-fluoro-benzenesulfonamide	DMIQ3VR	Discovery agent	N.A.	Investigative	[1]
4-Amino-3-iodo-benzenesulfonamide	DMCOYHR	Discovery agent	N.A.	Investigative	[1]
4-Hydrazino-benzenesulfonamide	DM49B18	Discovery agent	N.A.	Investigative	[1]
6-(aminomethyl)-2H-chromen-2-one	DMJU9TG	Discovery agent	N.A.	Investigative	[11]
6-(hydroxymethyl)-2H-chromen-2-one	DM5TOX2	Discovery agent	N.A.	Investigative	[11]
6-methyl-2-oxo-2H-chromene-3-carboxylic acid	DMZ6HQL	Discovery agent	N.A.	Investigative	[11]
7-(benzyloxy)-2H-chromen-2-one	DMTKFPW	Discovery agent	N.A.	Investigative	[11]
Aminocarbonyl dihydrogen phosphate	DMCLVOZ	Discovery agent	N.A.	Investigative	[13]
BENZOLAMIDE	DME5QPX	Discovery agent	N.A.	Investigative	[14]
Carbamoyl phosphate disodium	DMZYK1W	Discovery agent	N.A.	Investigative	[15]
CATECHIN	DMY38SB	Discovery agent	N.A.	Investigative	[4]
CATECHOL	DML0YEK	Discovery agent	N.A.	Investigative	[5]
CL-5343	DM9AFZ3	Solid tumour/cancer	2A00-2F9Z	Investigative	[16]
COUMARIN	DM0N8ZM	Discovery agent	N.A.	Investigative	[11]
Decane-1,10-diyl disulfamate	DM1ESVR	Discovery agent	N.A.	Investigative	[17]
Decyl sulfamate	DMIERWO	Discovery agent	N.A.	Investigative	[17]
ELLAGIC ACID	DMX8BS5	Discovery agent	N.A.	Investigative	[5]
Ethyl 7-methoxy-2-oxo-2H-chromene-3-carboxylate	DMWIB0V	Discovery agent	N.A.	Investigative	[11]
GALLICACID	DM6Y3A0	Discovery agent	N.A.	Investigative	[5]
HERNIARIN	DM9UASM	Discovery agent	N.A.	Investigative	[11]
Hexane-1,6-diamine	DMSHF0K	Discovery agent	N.A.	Investigative	[9]
Malonate sodium	DMAJDU7	Discovery agent	N.A.	Investigative	[7]
N-(5-ethyl-1,3,4-thiadiazol-2-yl)sulfamide	DMNQDLC	Discovery agent	N.A.	Investigative	[18]
N-(5-phenyl-1,3,4-thiadiazol-2-yl)sulfamide	DMA21WB	Discovery agent	N.A.	Investigative	[18]
N-(5-Sulfamoyl-[1,3,4]thiadiazol-2-yl)-benzamide	DMDZ9BY	Discovery agent	N.A.	Investigative	[12]
N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)sulfamide	DM5E7OC	Discovery agent	N.A.	Investigative	[18]
N-(phosphonacetyl)-L-aspartate	DMGHQJ8	Discovery agent	N.A.	Investigative	[13]
N-1,3,4-thiadiazol-2-ylsulfamide	DMJ10WH	Discovery agent	N.A.	Investigative	[18]
N-hydroxysulfonamides	DMJBC03	Discovery agent	N.A.	Investigative	[19]
N-[5-(ethylthio)-1,3,4-thiadiazol-2-yl]sulfamide	DMSI4PE	Discovery agent	N.A.	Investigative	[18]
N-[5-(methylthio)-1,3,4-thiadiazol-2-yl]sulfamide	DMXLJGR	Discovery agent	N.A.	Investigative	[18]
N1-(naphthalen-1-yl)ethane-1,2-diamine	DMYGCSV	Discovery agent	N.A.	Investigative	[9]
Octane-1,8-diyl disulfamate	DMBQMGH	Discovery agent	N.A.	Investigative	[17]
Octyl sulfamate	DM40ZCA	Discovery agent	N.A.	Investigative	[17]
P-Coumaric Acid	DMGJSVD	Discovery agent	N.A.	Investigative	[5]
Pentane-1,5-diamine	DMVPZG9	Discovery agent	N.A.	Investigative	[9]
Phenyl Boronic acid	DMFZH49	Discovery agent	N.A.	Investigative	[20]
Phenyl-phosphonic acid	DMYMNBL	Discovery agent	N.A.	Investigative	[13]
Phenylarsonic acid	DMFRA1Y	Discovery agent	N.A.	Investigative	[21]
SODIUM CITRATE	DMHPD2Y	Common cold	CA00	Investigative	[7]
Sodium phenylarsonate	DMXELBI	Discovery agent	N.A.	Investigative	[20]
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	DM1G4S9	Discovery agent	N.A.	Investigative	[15]
Sodium sulfamate	DMAMV6T	Discovery agent	N.A.	Investigative	[20]
Sodium trithiocarbonate	DM6WYGC	Discovery agent	N.A.	Investigative	[22]
SULFAMATE	DMF1589	Discovery agent	N.A.	Investigative	[21]
SYL-040003	DM7YB08	Ocular hypertension	9C61.01	Investigative	[23]
Syringic Acid	DM802V7	Discovery agent	N.A.	Investigative	[5]
Trecadrine	DMDX0VI	Discovery agent	N.A.	Investigative	[24]
Trisodium phosphate	DMPVI3A	Discovery agent	N.A.	Investigative	[15]
[Cu(CN)2]-	DMV6NP1	Discovery agent	N.A.	Investigative	[25]
[Fe(CN)6]4-	DMWGADP	Discovery agent	N.A.	Investigative	[25]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Breast cancer	2C82	Breast tissue	1.58E-77	-2.02	-1.77

References

• [1] Carbonic anhydrase inhibitors. Inhibition of the membrane-bound human and bovine isozymes IV with sulfonamides. Bioorg Med Chem Lett. 2005 Feb 15;15(4):1149-54.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] Carbonic anhydrase inhibitors: inhibition of mammalian isoforms I-XIV with a series of substituted phenols including paracetamol and salicylic acid. Bioorg Med Chem. 2008 Aug 1;16(15):7424-8.
• [4] Carbonic anhydrase inhibitors. Antioxidant polyphenols effectively inhibit mammalian isoforms I-XV. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5050-3.
• [5] Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I-XIV with a series of natural product polyphenols and phenolic acids. Bioorg Med Chem. 2010 Mar 15;18(6):2159-2164.
• [6] Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-r... Bioorg Med Chem Lett. 2008 Aug 1;18(15):4282-6.
• [7] Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with carboxylates. Bioorg Med Chem Lett. 2005 Feb 1;15(3):573-8.
• [8] Carbonic anhydrase inhibitors: crystallographic and solution binding studies for the interaction of a boron-containing aromatic sulfamide with mamm... Bioorg Med Chem Lett. 2010 Jun 15;20(12):3601-5.
• [9] Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule. J Med Chem. 2010 Aug 12;53(15):5511-22.
• [10] N-hydroxyurea--a versatile zinc binding function in the design of metalloenzyme inhibitors. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4316-20.
• [11] Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J Med Chem. 2010 Jan 14;53(1):335-44.
• [12] Carbonic anhydrase inhibitors: anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties. J Med Chem. 2002 Jan 17;45(2):312-20.
• [13] Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with organic phosphates and phosphonates. Bioorg Med Chem Lett. 2005 Mar 15;15(6):1683-6.
• [14] Carbonic anhydrase inhibitors: topically acting antiglaucoma sulfonamides incorporating esters and amides of 3- and 4-carboxybenzolamide. Bioorg Med Chem Lett. 2003 Sep 1;13(17):2867-73.
• [15] Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with phosphates, carbamoyl phosphate, and the phosphonate antiviral dru... Bioorg Med Chem Lett. 2004 Dec 6;14(23):5763-7.
• [16] Carbonic anhydrase inhibitors. The X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a l... Bioorg Med Chem Lett. 2010 Aug 1;20(15):4376-81.
• [17] Carbonic anhydrase inhibitors. Comparison of aliphatic sulfamate/bis-sulfamate adducts with isozymes II and IX as a platform for designing tight-bi... J Med Chem. 2009 Oct 8;52(19):5990-8.
• [18] Carbonic anhydrase inhibitors: 2-substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes ... Bioorg Med Chem Lett. 2008 Dec 15;18(24):6332-5.
• [19] Carbonic anhydrase inhibitors: inhibition of isozymes I, II and IV with N-hydroxysulfonamides--a novel class of intraocular pressure lowering agents. J Enzyme Inhib. 1998 Jul;13(4):267-84.
• [20] Carbonic anhydrase inhibitors: the membrane-associated isoform XV is highly inhibited by inorganic anions. Bioorg Med Chem Lett. 2009 Feb 15;19(4):1155-8.
• [21] Carbonic anhydrase inhibitors: inhibition of the membrane-bound human isozyme IV with anions. Bioorg Med Chem Lett. 2004 Dec 6;14(23):5769-73.
• [22] Carbonic anhydrase inhibitors. Inhibition of cytosolic isoforms I, II, III, VII and XIII with less investigated inorganic anions. Bioorg Med Chem Lett. 2009 Apr 1;19(7):1855-7.
• [23] 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: 2599).
• [24] Sulfenamido-sulfonamides as inhibitors of carbonic anhydrase isozymes I, II and IV. J Enzyme Inhib. 1997 Aug;12(3):175-90.
• [25] Carbonic anhydrase inhibitors. Inhibition of isozymes I, II, IV, V and IX with complex fluorides, chlorides and cyanides. Bioorg Med Chem Lett. 2005 Apr 1;15(7):1909-13.