Sulfasalazine (T3D2892)
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| Version | 2.0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Creation Date | 2009-07-21 20:27:39 UTC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Update Date | 2014-12-24 20:25:52 UTC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Accession Number | T3D2892 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Identification | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Common Name | Sulfasalazine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Class | Small Molecule | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | Sulfasalazine is only found in individuals that have used or taken this drug. It is a drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid (see mesalamine) released in the colon. (From Martindale, The Extra Pharmacopoeia, 30th ed, p907)The mode of action of Sulfasalazine or its metabolites, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under investigation, but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of Sulfasalazine, SP and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Compound Type |
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| Chemical Structure |  | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Synonyms |
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| Chemical Formula | C18H14N4O5S | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Average Molecular Mass | 398.393 g/mol | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Monoisotopic Mass | 398.068 g/mol | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CAS Registry Number | 599-79-1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| IUPAC Name | 2-hydroxy-5-[(E)-2-{4-[(pyridin-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzoic acid | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Traditional Name | sulfasalazine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SMILES | OC(=O)C1=C(O)C=CC(=C1)\N=N\C1=CC=C(C=C1)S(=O)(=O)NC1=CC=CC=N1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| InChI Identifier | InChI=1S/C18H14N4O5S/c23-16-9-6-13(11-15(16)18(24)25)21-20-12-4-7-14(8-5-12)28(26,27)22-17-3-1-2-10-19-17/h1-11,23H,(H,19,22)(H,24,25)/b21-20+ | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| InChI Key | InChIKey=NCEXYHBECQHGNR-QZQOTICOSA-N | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Chemical Taxonomy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | belongs to the class of organic compounds known as azobenzenes. These are organonitrogen aromatic compounds that contain a central azo group, where each nitrogen atom is conjugated to a benzene ring. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kingdom | Organic compounds | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Super Class | Organoheterocyclic compounds | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Class | Azobenzenes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sub Class | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Direct Parent | Azobenzenes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative Parents |
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| Substituents |
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| Molecular Framework | Aromatic heteromonocyclic compounds | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| External Descriptors |
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| Biological Properties | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Status | Detected and Not Quantified | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Origin | Exogenous | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cellular Locations |
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| Biofluid Locations | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tissue Locations | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pathways | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Applications | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biological Roles | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Chemical Roles | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Physical Properties | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| State | Solid | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Appearance | White powder. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Experimental Properties |
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| Predicted Properties |
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| Spectra | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Spectra |
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| Toxicity Profile | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Route of Exposure | Oral | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mechanism of Toxicity | The mode of action of Sulfasalazine or its metabolites, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under investigation, but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of Sulfasalazine, SP and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Metabolism | Route of Elimination: The majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA with the feces. Half Life: 5-10 hours | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Toxicity Values | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lethal Dose | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Carcinogenicity (IARC Classification) | 2B, possibly carcinogenic to humans. (3) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Uses/Sources | Used primarily as an anti-inflammatory agent in the treatment of inflammatory bowel disease as well as for rheumatoid arthritis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Minimum Risk Level | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Health Effects | Sulfasalazine in rare cases can cause severe depression in young males. Immune thrombocytopenia has been reported. [Wikipedia] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Symptoms | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment | Gastric lavage or emesis plus catharsis as indicated. Alkalinize urine. If kidney function is normal, force fluids. If anuria is present, restrict fluids and salt, and treat appropriately. Catheterization of the ureters may be indicated for complete renal blockage by crystals. The low molecular weight of sulfasalazine and its metabolites may facilitate their removal by dialysis. (2) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Normal Concentrations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Abnormal Concentrations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Not Available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| External Links | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DrugBank ID | DB00795 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HMDB ID | HMDB14933 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PubChem Compound ID | 5359476 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ChEMBL ID | CHEMBL421 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ChemSpider ID | 4510284 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| KEGG ID | C07316 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| UniProt ID | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| OMIM ID | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ChEBI ID | 9334 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BioCyc ID | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CTD ID | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Stitch ID | Sulfasalazine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PDB ID | SAS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ACToR ID | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Wikipedia Link | Sulfasalazine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| References | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Synthesis Reference | Not Available | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MSDS | Link | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| General References | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Regulation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Up-Regulated Genes |
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| Down-Regulated Genes |
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Targets
- General Function:
- Zinc ion binding
- Specific Function:
- Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity).
- Gene Name:
- PPARG
- Uniprot ID:
- P37231
- Molecular Weight:
- 57619.58 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| AC50 | 2.28 uM | NVS_NR_hPPARg | Novascreen |
References
- Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, Auwerx J, Metzger D, Wahli W, Desvergne B, Naccari GC, Chavatte P, Farce A, Bulois P, Cortot A, Colombel JF, Desreumaux P: Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med. 2005 Apr 18;201(8):1205-15. Epub 2005 Apr 11. [15824083 ]
- Schwab M, Reynders V, Loitsch S, Shastri YM, Steinhilber D, Schroder O, Stein J: PPARgamma is involved in mesalazine-mediated induction of apoptosis and inhibition of cell growth in colon cancer cells. Carcinogenesis. 2008 Jul;29(7):1407-14. doi: 10.1093/carcin/bgn118. Epub 2008 Jun 9. [18544567 ]
- Linard C, Gremy O, Benderitter M: Reduction of peroxisome proliferation-activated receptor gamma expression by gamma-irradiation as a mechanism contributing to inflammatory response in rat colon: modulation by the 5-aminosalicylic acid agonist. J Pharmacol Exp Ther. 2008 Mar;324(3):911-20. Epub 2007 Dec 12. [18077625 ]
- Desreumaux P, Ghosh S: Review article: mode of action and delivery of 5-aminosalicylic acid - new evidence. Aliment Pharmacol Ther. 2006 Sep;24 Suppl 1:2-9. [16939423 ]
- Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
- General Function:
- Prostaglandin-endoperoxide synthase activity
- Specific Function:
- Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.
- Gene Name:
- PTGS2
- Uniprot ID:
- P35354
- Molecular Weight:
- 68995.625 Da
References
- Mifflin RC, Saada JI, Di Mari JF, Valentich JD, Adegboyega PA, Powell DW: Aspirin-mediated COX-2 transcript stabilization via sustained p38 activation in human intestinal myofibroblasts. Mol Pharmacol. 2004 Feb;65(2):470-8. [14742690 ]
- Generini S, Fiori G, Matucci Cerinic M: Therapy of spondylarthropathy in inflammatory bowel disease. Clin Exp Rheumatol. 2002 Nov-Dec;20(6 Suppl 28):S88-94. [12463455 ]
- Distrutti E, Sediari L, Mencarelli A, Renga B, Orlandi S, Russo G, Caliendo G, Santagada V, Cirino G, Wallace JL, Fiorucci S: 5-Amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester (ATB-429), a hydrogen sulfide-releasing derivative of mesalamine, exerts antinociceptive effects in a model of postinflammatory hypersensitivity. J Pharmacol Exp Ther. 2006 Oct;319(1):447-58. Epub 2006 Jul 19. [16855178 ]
- Cipolla G, Crema F, Sacco S, Moro E, de Ponti F, Frigo G: Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: current perspectives. Pharmacol Res. 2002 Jul;46(1):1-6. [12208114 ]
- Pruzanski W, Stefanski E, Vadas P, Ramamurthy NS: Inhibition of extracellular release of proinflammatory secretory phospholipase A2 (sPLA2) by sulfasalazine: a novel mechanism of anti-inflammatory activity. Biochem Pharmacol. 1997 Jun 15;53(12):1901-7. [9256165 ]
- General Function:
- Iron ion binding
- Specific Function:
- Catalyzes the first step in leukotriene biosynthesis, and thereby plays a role in inflammatory processes.
- Gene Name:
- ALOX5
- Uniprot ID:
- P09917
- Molecular Weight:
- 77982.595 Da
References
- Nielsen OH, Bukhave K, Elmgreen J, Ahnfelt-Ronne I: Inhibition of 5-lipoxygenase pathway of arachidonic acid metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid. Dig Dis Sci. 1987 Jun;32(6):577-82. [2882965 ]
- Allgayer H, Eisenburg J, Paumgartner G: Soybean lipoxygenase inhibition: studies with the sulphasalazine metabolites N-acetylaminosalicylic acid, 5-aminosalicylic acid and sulphapyridine. Eur J Clin Pharmacol. 1984;26(4):449-51. [6428914 ]
- Sircar JC, Schwender CF, Carethers ME: Inhibition of soybean lipoxygenase by sulfasalazine and 5-aminosalicylic acid: a possible mode of action in ulcerative colitis. Biochem Pharmacol. 1983 Jan 1;32(1):170-2. [6131674 ]
- General Function:
- Metal ion binding
- Specific Function:
- Plays a major role in ketone body metabolism.
- Gene Name:
- ACAT1
- Uniprot ID:
- P24752
- Molecular Weight:
- 45199.2 Da
References
- General Function:
- Cystine:glutamate antiporter activity
- Specific Function:
- Sodium-independent, high-affinity exchange of anionic amino acids with high specificity for anionic form of cystine and glutamate.
- Gene Name:
- SLC7A11
- Uniprot ID:
- Q9UPY5
- Molecular Weight:
- 55422.44 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| IC50 | 30 uM | Not Available | BindingDB 50097125 |
References
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
- Shukla K, Thomas AG, Ferraris DV, Hin N, Sattler R, Alt J, Rojas C, Slusher BS, Tsukamoto T: Inhibition of xc(-) transporter-mediated cystine uptake by sulfasalazine analogs. Bioorg Med Chem Lett. 2011 Oct 15;21(20):6184-7. doi: 10.1016/j.bmcl.2011.07.081. Epub 2011 Aug 12. [21889337 ]
- General Function:
- Scaffold protein binding
- Specific Function:
- Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor (PubMed:15084260).
- Gene Name:
- CHUK
- Uniprot ID:
- O15111
- Molecular Weight:
- 84638.88 Da
References
- Weber CK, Liptay S, Wirth T, Adler G, Schmid RM: Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology. 2000 Nov;119(5):1209-18. [11054378 ]
- Allgayer H: Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther. 2003 Sep;18 Suppl 2:10-4. [12950415 ]
- General Function:
- Scaffold protein binding
- Specific Function:
- Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.
- Gene Name:
- IKBKB
- Uniprot ID:
- O14920
- Molecular Weight:
- 86563.245 Da
References
- Weber CK, Liptay S, Wirth T, Adler G, Schmid RM: Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology. 2000 Nov;119(5):1209-18. [11054378 ]
- Allgayer H: Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther. 2003 Sep;18 Suppl 2:10-4. [12950415 ]
- General Function:
- Zinc ion binding
- Specific Function:
- Reversible hydration of carbon dioxide. Can hydrates cyanamide to urea.
- Gene Name:
- CA1
- Uniprot ID:
- P00915
- Molecular Weight:
- 28870.0 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| Inhibitory | 6.87 uM | Not Available | BindingDB 50097125 |
| IC50 | 3.04 uM | Not Available | BindingDB 50097125 |
References
- Bayram E, Senturk M, Kufrevioglu OI, Supuran CT: In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II. Bioorg Med Chem. 2008 Oct 15;16(20):9101-5. doi: 10.1016/j.bmc.2008.09.028. Epub 2008 Sep 13. [18819808 ]
- General Function:
- Zinc ion binding
- Specific Function:
- Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye. Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption. Stimulates the chloride-bicarbonate exchange activity of SLC26A6.
- Gene Name:
- CA2
- Uniprot ID:
- P00918
- Molecular Weight:
- 29245.895 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| Inhibitory | 8.72 uM | Not Available | BindingDB 50097125 |
| IC50 | 4.49 uM | Not Available | BindingDB 50097125 |
References
- Bayram E, Senturk M, Kufrevioglu OI, Supuran CT: In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II. Bioorg Med Chem. 2008 Oct 15;16(20):9101-5. doi: 10.1016/j.bmc.2008.09.028. Epub 2008 Sep 13. [18819808 ]
- General Function:
- S100 protein binding
- Specific Function:
- Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro.
- Gene Name:
- FGF1
- Uniprot ID:
- P05230
- Molecular Weight:
- 17459.58 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| Dissociation | 609 uM | Not Available | BindingDB 50097125 |
References
- Bytheway I, Cochran S: Validation of molecular docking calculations involving FGF-1 and FGF-2. J Med Chem. 2004 Mar 25;47(7):1683-93. [15027859 ]
- General Function:
- Receptor binding
- Specific Function:
- PA2 catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides, this releases glycerophospholipids and arachidonic acid that serve as the precursors of signal molecules.
- Gene Name:
- PLA2G1B
- Uniprot ID:
- P04054
- Molecular Weight:
- 16359.535 Da
References
- Pruzanski W, Stefanski E, Vadas P, Ramamurthy NS: Inhibition of extracellular release of proinflammatory secretory phospholipase A2 (sPLA2) by sulfasalazine: a novel mechanism of anti-inflammatory activity. Biochem Pharmacol. 1997 Jun 15;53(12):1901-7. [9256165 ]
- General Function:
- Prostaglandin-endoperoxide synthase activity
- Specific Function:
- Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells.
- Gene Name:
- PTGS1
- Uniprot ID:
- P23219
- Molecular Weight:
- 68685.82 Da
References
- Allgayer H: Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther. 2003 Sep;18 Suppl 2:10-4. [12950415 ]
- General Function:
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function:
- Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
- Gene Name:
- SLCO1B1
- Uniprot ID:
- Q9Y6L6
- Molecular Weight:
- 76447.99 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| Inhibitory | 0.53 uM | Not Available | BindingDB 50097125 |
| IC50 | 0.56 uM | Not Available | BindingDB 50097125 |
References
- Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [22541068 ]
- General Function:
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function:
- Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver.
- Gene Name:
- SLCO1B3
- Uniprot ID:
- Q9NPD5
- Molecular Weight:
- 77402.175 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| Inhibitory | 11 uM | Not Available | BindingDB 50097125 |
| IC50 | 12 uM | Not Available | BindingDB 50097125 |
References
- Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [22541068 ]
- General Function:
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function:
- Mediates the Na(+)-independent transport of organic anions such as taurocholate, the prostaglandins PGD2, PGE1, PGE2, leukotriene C4, thromboxane B2 and iloprost.
- Gene Name:
- SLCO2B1
- Uniprot ID:
- O94956
- Molecular Weight:
- 76709.98 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| Inhibitory | 3 uM | Not Available | BindingDB 50097125 |
| IC50 | 3 uM | Not Available | BindingDB 50097125 |
References
- Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [22541068 ]
- General Function:
- Zinc ion binding
- Specific Function:
- Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
- Gene Name:
- AR
- Uniprot ID:
- P10275
- Molecular Weight:
- 98987.9 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| AC50 | 2.70 uM | NVS_NR_hAR | Novascreen |
References
- Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
- General Function:
- Thromboxane a2 receptor activity
- Specific Function:
- Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C. Isoform 1 activates adenylyl cyclase. Isoform 2 inhibits adenylyl cyclase.
- Gene Name:
- TBXA2R
- Uniprot ID:
- P21731
- Molecular Weight:
- 37430.69 Da
Binding/Activity Constants
| Type | Value | Assay Type | Assay Source |
|---|---|---|---|
| AC50 | 7.90 uM | NVS_GPCR_hTXA2 | Novascreen |
References
- Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]