Target Information

Target General Infomation
Target ID
T53378
Former ID
TTDR00209
Target Name
Carbonic anhydrase IV
Gene Name
CA4
Synonyms
CAIV; Carbonate dehydratase IV; Carbonic anhydrase 4; CA4
Target Type
Successful
Disease Breast cancer [ICD9: 174, 175; ICD10: C50]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Ocular hypertension [ICD9: 365.04; ICD10: H40.0]
Open-angle glaucoma; Ocular hypertension [ICD9: 365, 365.04; ICD10: H40-H42, H40.0]
Function
Reversible hydration of carbon dioxide. 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.
BioChemical Class
Carbon-oxygen lyases
Target Validation
T53378
UniProt ID
P22748
EC Number
EC 4.2.1.1
Sequence
MRMLLALLALSAARPSASAESHWCYEVQAESSNYPCLVPVKWGGNCQKDRQSPINIVTTK
AKVDKKLGRFFFSGYDKKQTWTVQNNGHSVMMLLENKASISGGGLPAPYQAKQLHLHWSD
LPYKGSEHSLDGEHFAMEMHIVHEKEKGTSRNVKEAQDPEDEIAVLAFLVEAGTQVNEGF
QPLVEALSNIPKPEMSTTMAESSLLDLLPKEEKLRHYFRYLGSLTTPTCDEKVVWTVFRE
PIQLHREQILAFSQKLYYDKEQTVSMKDNVRPLQQLGQRTVIKSGAPGRPLPWALPALLG
PMLACLLAGFLR
Structure
1ZNC; 3F7B; 3F7U; 3FW3
Drugs and Mode of Action
Drug(s) Brinzolamide Drug Info Approved Open-angle glaucoma; Ocular hypertension [536361], [541878]
MAFENIDE Drug Info Approved Bacterial infection [530765]
SALICYLATE Drug Info Phase 4 Discovery agent [524105]
Curcumin Drug Info Phase 3 Cancer [532348], [542031]
PARABEN Drug Info Phase 3 Discovery agent [524059]
PHENOL Drug Info Phase 2/3 Discovery agent [525296]
COUMATE Drug Info Phase 2 Breast cancer [531371]
SULFAMIDE Drug Info Phase 1 Discovery agent [524873]
SPERMINE Drug Info Terminated Discovery agent [542107], [546483]
Inhibitor 1-(3,4-dichlorophenyl)-3-hydroxyurea Drug Info [528240]
2,4-Disulfamyltrifluoromethylaniline Drug Info [527415]
2-oxo-2H-chromene-3-carboxylic acid Drug Info [530514]
2-Propyl-pentanoic acid 4-sulfamoyl-benzyl ester Drug Info [526241]
2-Propyl-pentanoic acid 4-sulfamoyl-benzylamide Drug Info [526241]
3-Amino-benzenesulfonamide Drug Info [527415]
4-(2-Amino-ethyl)-benzenesulfonamide Drug Info [527415]
4-Amino-3-bromo-benzenesulfonamide Drug Info [527415]
4-Amino-3-chloro-benzenesulfonamide Drug Info [527415]
4-Amino-3-fluoro-benzenesulfonamide Drug Info [527415]
4-Amino-3-iodo-benzenesulfonamide Drug Info [527415]
4-Hydrazino-benzenesulfonamide Drug Info [527415]
5-amino-1,3,4-thiadiazole-2-sulfonamide Drug Info [531013]
6-(aminomethyl)-2H-chromen-2-one Drug Info [530514]
6-(hydroxymethyl)-2H-chromen-2-one Drug Info [530514]
6-methyl-2-oxo-2H-chromene-3-carboxylic acid Drug Info [530514]
7-(benzyloxy)-2H-chromen-2-one Drug Info [530514]
Aminocarbonyl dihydrogen phosphate Drug Info [527462]
BENZOLAMIDE Drug Info [526877]
Carbamoyl phosphate disodium Drug Info [527259]
CATECHIN Drug Info [531068]
CATECHOL Drug Info [530751]
COUMARIN Drug Info [530514]
COUMATE Drug Info [529605]
Curcumin Drug Info [531068]
Decane-1,10-diyl disulfamate Drug Info [530359]
Decyl sulfamate Drug Info [530359]
ELLAGIC ACID Drug Info [530751]
Ethyl 7-methoxy-2-oxo-2H-chromene-3-carboxylate Drug Info [530514]
FERULIC ACID Drug Info [530751]
GALLICACID Drug Info [530751]
HERNIARIN Drug Info [530514]
Hexane-1,6-diamine Drug Info [530998]
MAFENIDE Drug Info [527415]
Malonate sodium Drug Info [527390]
N-(5-ethyl-1,3,4-thiadiazol-2-yl)sulfamide Drug Info [529794]
N-(5-phenyl-1,3,4-thiadiazol-2-yl)sulfamide Drug Info [529794]
N-(5-Sulfamoyl-[1,3,4]thiadiazol-2-yl)-benzamide Drug Info [526241]
N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)sulfamide Drug Info [529794]
N-1,3,4-thiadiazol-2-ylsulfamide Drug Info [529794]
N-hydroxysulfonamides Drug Info [538135]
N-[5-(ethylthio)-1,3,4-thiadiazol-2-yl]sulfamide Drug Info [529794]
N-[5-(methylthio)-1,3,4-thiadiazol-2-yl]sulfamide Drug Info [529794]
N1-(naphthalen-1-yl)ethane-1,2-diamine Drug Info [530998]
Octane-1,8-diyl disulfamate Drug Info [530359]
Octyl sulfamate Drug Info [530359]
P-Coumaric Acid Drug Info [530751]
PARABEN Drug Info [530751]
Pentane-1,5-diamine Drug Info [530998]
PHENOL Drug Info [531068]
Phenyl Boronic acid Drug Info [529905]
Phenyl-phosphonic acid Drug Info [527462]
Phenylarsonic acid Drug Info [527260]
PYRUVATE SODIUM Drug Info [527390]
SALICYLATE Drug Info [529562]
SODIUM CITRATE Drug Info [527390]
Sodium phenylarsonate Drug Info [529905]
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS Drug Info [527259]
Sodium sulfamate Drug Info [529905]
Sodium trithiocarbonate Drug Info [530003]
SPARFOSIC ACID Drug Info [527462]
SPERMINE Drug Info [530998]
SULFAMATE Drug Info [527260]
SULFAMIDE Drug Info [530922]
Sulfenamido-sulfonamides Drug Info [538055]
Syringic Acid Drug Info [530751]
Trisodium phosphate Drug Info [527259]
[Cu(CN)2]- Drug Info [527492]
[Fe(CN)6]4- Drug Info [527492]
Modulator Brinzolamide Drug Info [556264]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Nitrogen metabolism
Proximal tubule bicarbonate reclamation
Reactome Erythrocytes take up carbon dioxide and release oxygen
Erythrocytes take up oxygen and release carbon dioxide
Reversible hydration of carbon dioxide
WikiPathways Reversible Hydration of Carbon Dioxide
Uptake of Carbon Dioxide and Release of Oxygen by Erythrocytes
Uptake of Oxygen and Release of Carbon Dioxide by Erythrocytes
References
Ref 524059ClinicalTrials.gov (NCT01688479) Trial Comparing Calendula Officinalis With Aqueous Cream "Essex" to Treat Skin Reactions From Radiotherapy of Breast Cancer. U.S. National Institutes of Health.
Ref 524105ClinicalTrials.gov (NCT01712295) 17% Salicylate Versus 17% Salicylate-Ethyl Pyruvate for Plantar Foot Warts. U.S. National Institutes of Health.
Ref 524873ClinicalTrials.gov (NCT02216669) Trial to Determine Optimal Phase II Dose of the Oral Dual CAIX Inhibitor/ Radiosensitizer. U.S. National Institutes of Health.
Ref 525296ClinicalTrials.gov (NCT02527187) Determination of the Sensitivity and Specificity of Prick Test Betula Verrucosa.
Ref 530765J Med Chem. 2010 Apr 8;53(7):2913-26.Sulfonamide linked neoglycoconjugates--a new class of inhibitors for cancer-associated carbonic anhydrases.
Ref 531371Irosustat: a first-generation steroid sulfatase inhibitor in breast cancer. Expert Rev Anticancer Ther. 2011 Feb;11(2):179-83.
Ref 532348Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst. 2013;30(4):331-68.
Ref 536361Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20.
Ref 541878(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: 6797).
Ref 542031(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: 7000).
Ref 542107(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: 710).
Ref 546483Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008464)
Ref 526241J Med Chem. 2002 Jan 17;45(2):312-20.Carbonic anhydrase inhibitors: anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties.
Ref 526877Bioorg Med Chem Lett. 2003 Sep 1;13(17):2867-73.Carbonic anhydrase inhibitors: topically acting antiglaucoma sulfonamides incorporating esters and amides of 3- and 4-carboxybenzolamide.
Ref 527259Bioorg Med Chem Lett. 2004 Dec 6;14(23):5763-7.Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with phosphates, carbamoyl phosphate, and the phosphonate antiviral drug foscarnet.
Ref 527260Bioorg Med Chem Lett. 2004 Dec 6;14(23):5769-73.Carbonic anhydrase inhibitors: inhibition of the membrane-bound human isozyme IV with anions.
Ref 527390Bioorg Med Chem Lett. 2005 Feb 1;15(3):573-8.Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with carboxylates.
Ref 527415Bioorg Med Chem Lett. 2005 Feb 15;15(4):1149-54.Carbonic anhydrase inhibitors. Inhibition of the membrane-bound human and bovine isozymes IV with sulfonamides.
Ref 527462Bioorg Med Chem Lett. 2005 Mar 15;15(6):1683-6.Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with organic phosphates and phosphonates.
Ref 527492Bioorg Med Chem Lett. 2005 Apr 1;15(7):1909-13.Carbonic anhydrase inhibitors. Inhibition of isozymes I, II, IV, V and IX with complex fluorides, chlorides and cyanides.
Ref 528240Bioorg Med Chem Lett. 2006 Aug 15;16(16):4316-20. Epub 2006 Jun 12.N-hydroxyurea--a versatile zinc binding function in the design of metalloenzyme inhibitors.
Ref 529562Bioorg Med Chem. 2008 Aug 1;16(15):7424-8. Epub 2008 Jun 13.Carbonic anhydrase inhibitors: inhibition of mammalian isoforms I-XIV with a series of substituted phenols including paracetamol and salicylic acid.
Ref 529605Bioorg Med Chem Lett. 2008 Aug 1;18(15):4282-6. Epub 2008 Jul 5.Carbonic anhydrase inhibitors. Interaction of the antitumor sulfamate EMD 486019 with twelve mammalian carbonic anhydrase isoforms: Kinetic and X-ray crystallographic studies.
Ref 529794Bioorg Med Chem Lett. 2008 Dec 15;18(24):6332-5. Epub 2008 Nov 1.Carbonic anhydrase inhibitors: 2-substituted-1,3,4-thiadiazole-5-sulfamides act as powerful and selective inhibitors of the mitochondrial isozymes VA and VB over the cytosolic and membrane-associated carbonic anhydrases I, II and IV.
Ref 529905Bioorg Med Chem Lett. 2009 Feb 15;19(4):1155-8. Epub 2008 Dec 25.Carbonic anhydrase inhibitors: the membrane-associated isoform XV is highly inhibited by inorganic anions.
Ref 530003Bioorg Med Chem Lett. 2009 Apr 1;19(7):1855-7. Epub 2009 Feb 26.Carbonic anhydrase inhibitors. Inhibition of cytosolic isoforms I, II, III, VII and XIII with less investigated inorganic anions.
Ref 530359J Med Chem. 2009 Oct 8;52(19):5990-8.Carbonic anhydrase inhibitors. Comparison of aliphatic sulfamate/bis-sulfamate adducts with isozymes II and IX as a platform for designing tight-binding, more isoform-selective inhibitors.
Ref 530514J Med Chem. 2010 Jan 14;53(1):335-44.Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins.
Ref 530751Bioorg Med Chem. 2010 Mar 15;18(6):2159-64. Epub 2010 Feb 6.Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I-XIV with a series of natural product polyphenols and phenolic acids.
Ref 530922Bioorg Med Chem Lett. 2010 Jun 15;20(12):3601-5. Epub 2010 Apr 28.Carbonic anhydrase inhibitors: crystallographic and solution binding studies for the interaction of a boron-containing aromatic sulfamide with mammalian isoforms I-XV.
Ref 530998J Med Chem. 2010 Aug 12;53(15):5511-22.Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule.
Ref 531013Bioorg Med Chem Lett. 2010 Aug 1;20(15):4376-81. Epub 2010 Jun 17.Carbonic anhydrase inhibitors. The X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamideresides in a less utilized binding pocket than most hydrophobic inhibitors.
Ref 531068Bioorg Med Chem Lett. 2010 Sep 1;20(17):5050-3. Epub 2010 Jul 13.Carbonic anhydrase inhibitors. Antioxidant polyphenols effectively inhibit mammalian isoforms I-XV.
Ref 538055Sulfenamido-sulfonamides as inhibitors of carbonic anhydrase isozymes I, II and IV. J Enzyme Inhib. 1997 Aug;12(3):175-90.
Ref 538135Carbonic 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.
Ref 543655(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).
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

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