Drugbank Logo

Showing drug card for Thalidomide (DB01041)

Legend: drug field target field enzyme field

for drugs
Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-06-23 18:06:45
Primary Accession Number DB01041
Secondary Accession Number
  • APRD01251
Name Thalidomide
Drug Type
  • Approved
  • Investigational
  • Small Molecule
  • Withdrawn
Description A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. [PubChem]
Synonyms
  1. N-Phthalimidoglutamic acid imide
  2. N-Phthaloylglutamimide
  3. N-Phthalylglutamic acid imide
  4. Thalidomine USP26
  5. alpha-phthalimidoglutarimide
  6. thalidomide
Brand Names
  1. Algosediv
  2. Asidon 3
  3. Asmadion
  4. Asmaval
  5. Bonbrain
  6. Bonbrrin
  7. Calmore
  8. Calmorex
  9. Contergan
  10. Corronarobetin
  11. Distaval
  12. Distaxal
  13. Distoval
  14. Ectiluran
  15. Enterosediv
  16. Gastrinide
  17. Glupan
  18. Glutanon
  19. Grippex
  20. Hippuzon
  21. Imida-Lab
  22. Imidan
  23. Imidene
  24. Isomin
  25. Kedavon
  26. Kevadon
  27. Lulamin
  28. Neaufatin
  29. Neo
  30. Neosedyn
  31. Neosydyn
  32. Nerosedyn
  33. Neufatin
  34. Neurodyn
  35. Neurosedin
  36. Neurosedym
  37. Neurosedyn
  38. Nevrodyn
  39. Nibrol
  40. Noctosediv
  41. Noxodyn
  42. Pangul
  43. Pantosediv
  44. Poly-Giron
  45. Polygripan
  46. Predni-Sediv
  47. Pro-ban M
  48. Profarmil
  49. Psycholiquid
  50. Psychotablets
  51. Quetimid
  52. Quietoplex
  53. Sandormin
  54. Sedalis
  55. Sedalis sedi-lab
  56. Sedimide
  57. Sedin
  58. Sedisperil
  59. Sedoval
  60. Shin-naito S
  61. Shinnibrol
  62. Sleepan
  63. Slipro
  64. Softenil
  65. Softenon
  66. Talargan
  67. Talimol
  68. Talismol
  69. Telagan
  70. Telargan
  71. Telargean
  72. Tensival
  73. Thalin
  74. Thalinette
  75. Thalomid
  76. Theophilcholine
  77. Valgis
  78. Valgraine
  79. Yodomin
Brand Mixtures Not Available
Chemical IUPAC Name 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
Chemical Formula C13H10N2O4
Chemical Structure Structure
CAS Registry Number 50-35-1
InChI Identifier InChI=1/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)/f/h14H
InChI Key UEJJHQNACJXSKW-YHMJCDSICW
KEGG Drug D00754 Link Image
KEGG Compound C07910 Link Image
PubChem Compound 5426 Link Image
PubChem Substance 10112 Link Image
ChEBI ID Not Available
PharmGKB ID PA451644 Link Image
HET ID Not Available
GenBank ID Not Available
Drug ID Number [DIN] Not Available
RxList Link http://www.rxlist.com/cgi/generic2/thalidom.htm Link Image
PDRhealth Link Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Thalidomide Link Image
FDA Label
Material Safety Data Sheet (MSDS)
Synthesis Reference Not Available
Average Molecular Weight 258.2295
Monoisotopic Molecular Weight 258.0641
State Solid
Melting Point 270 oC
Experimental Water Solubility 545 mg/L Source: PhysProp
Predicted Water Solubility 2.55e+00 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity 0.3 Source: PhysProp
Predicted LogP 0.43 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -2.01 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric SMILES O=C1CC[C@@H](N2C(=O)C3=CC=CC=C3C2=O)C(=O)N1
Canonical SMILES O=C1CCC(N2C(=O)C3=CC=CC=C3C2=O)C(=O)N1
Drug Category
  • Angiogenesis Inhibitors
  • Immunosuppressive Agents
  • Leprostatic Agents
  • Teratogens
ATC Codes
AHFS Codes Not Available
Indication For the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Also for use as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.
Pharmacology Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: one enantiomer is effective against morning sickness, and the other is teratogenic. The enantiomers are converted to each other in vivo. That is, if a human is given D-thalidomide or L-thalidomide, both isomers can be found in the serum. Hence, administering only one enantiomer will not prevent the teratogenic effect in humans.
Mechanism of Action In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-a in patients with ENL, however, it has also been shown to increase plasma TNF-a levels in HIV-seropositive patients.
Absorption The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations (Tmax) ranged from 2.9 to 5.7 hours indicating that thalidomide is slowly absorbed from the gastrointestinal tract.
Toxicity The R-configuration and the S-configuration are more toxic individually than the racemic mixture. The LD50 could not be established in mice for racemic thalidomide, whereas LD50 values for the R and S configurations are reported to be 0.4 to 0.7 g/kg and 0.5 to 1.5 g/kg, respectively.
Protein Binding 55% and 66% for the (+)R and (−)S enantiomers, respectively.
Biotransformation Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. Thalidomide may be metabolized hepatically by enzymes of the cytochrome P450 enzyme system. The end product of metabolism, phthalic acid, is excreted as a glycine conjugate.
Half Life The mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing.
Dosage Forms
Form Route
Capsule Oral
Patient Information Show Link Image
Contraindications Show Link Image
Interactions Show Link Image
Drug Interactions
Drug Interaction
Abatacept Thalidomide may increase the adverse effects of Abatacept. Increased risk of serious infection. Concomitant therapy should be avoided.
Amikacin Thalidomide increases the renal toxicity of the aminoglycoside
Anakinra Thalidomide may increase the adverse effects of Anakinra. Increased risk of serious infection. Concomitant therapy should be avoided.
Dexamethasone Increased risk of dermatologic adverse effects and venous thromboembolic events (VTE). Consider VTE prophylaxis during concomitant therapy and monitor for adverse dematologic effects.
Gentamicin Thalidomide increases the renal toxicity of the aminoglycoside
Natalizumab Thalidomide may increase the adverse effects of Natalizumab. Concurrent administration should be avoided due to increased risk of infection.
Netilmicin Thalidomide increases the renal toxicity of the aminoglycoside
Tobramycin Thalidomide increases the renal toxicity of the aminoglycoside
rilonacept Thalidomide may increase the adverse effects of Rilonacept. Increased risk of serious infection. Concomitant therapy should be avoided.
Food Interactions Not Available
Pathways Not Available
General References
  1. Wikipedia Link Image
  2. RxList Link Image
Organisms Affected
  • Humans and other mammals
Phase 1 Metabolizing Enzymes
  1. Cytochrome P450 2C19 (CYP2C19)
Targets
  1. Prostaglandin G/H synthase 2
  2. Tumor necrosis factor
  3. Nuclear factor NF-kappa-B p105 subunit
Phase 1 Metabolizing Enzyme 1 [top]
Enzyme 1 Name Cytochrome P450 2C19 (CYP2C19)
Enzyme 1 Gene Name CYP2C19
Enzyme 1 SwissProt ID P33261 Link Image
Enzyme 1 SNPs SNPJam Report Link Image
Enzyme 1 Protein Sequence >sp|P33261|CP2CJ_HUMAN Cytochrome P450 2C19 (EC 1.14.13.80) 
MDPFVVLVLCLSCLLLLSIWRQSSGRGKLPPGPTPLPVIGNILQIDIKDVSKSLTNLSKI
YGPVFTLYFGLERMVVLHGYEVVKEALIDLGEEFSGRGHFPLAERANRGFGIVFSNGKRW
KEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICS
IIFQKRFDYKDQQFLNLMEKLNENIRIVSTPWIQICNNFPTIIDYFPGTHNKLLKNLAFM
ESDILEKVKEHQESMDINNPRDFIDCFLIKMEKEKQNQQSEFTIENLVITAADLLGAGTE
TTSTTLRYALLLLLKHPEVTAKVQEEIERVVGRNRSPCMQDRGHMPYTDAVVHEVQRYID
LIPTSLPHAVTCDVKFRNYLIPKGTTILTSLTSVLHDNKEFPNPEMFDPRHFLDEGGNFK
KSNYFMPFSAGKRICVGEGLARMELFLFLTFILQNFNLKSLIDPKDLDTTPVVNGFASVP
PFYQLCFIPV
Drug Target 1 [top]
Target 1 ID 290
Target 1 Name Prostaglandin G/H synthase 2
Target 1 Synonyms
  1. COX-2
  2. Cyclooxygenase- 2
  3. EC 1.14.99.1
  4. PGH synthase 2
  5. PGHS-2
  6. PHS II
  7. Prostaglandin G/H synthase 2 precursor
  8. Prostaglandin H2 synthase 2
  9. Prostaglandin-endoperoxide synthase 2
Target 1 Gene Name PTGS2
Target 1 Protein Sequence >Prostaglandin G/H synthase 2 precursor 
MLARALLLCAVLALSHTANPCCSHPCQNRGVCMSVGFDQYKCDCTRTGFYGENCSTPEFL
TRIKLFLKPTPNTVHYILTHFKGFWNVVNNIPFLRNAIMSYVLTSRSHLIDSPPTYNADY
GYKSWEAFSNLSYYTRALPPVPDDCPTPLGVKGKKQLPDSNEIVEKLLLRRKFIPDPQGS
NMMFAFFAQHFTHQFFKTDHKRGPAFTNGLGHGVDLNHIYGETLARQRKLRLFKDGKMKY
QIIDGEMYPPTVKDTQAEMIYPPQVPEHLRFAVGQEVFGLVPGLMMYATIWLREHNRVCD
VLKQEHPEWGDEQLFQTSRLILIGETIKIVIEDYVQHLSGYHFKLKFDPELLFNKQFQYQ
NRIAAEFNTLYHWHPLLPDTFQIHDQKYNYQQFIYNNSILLEHGITQFVESFTRQIAGRV
AGGRNVPPAVQKVSQASIDQSRQMKYQSFNEYRKRFMLKPYESFEELTGEKEMSAELEAL
YGDIDAVELYPALLVEKPRPDAIFGETMVEVGAPFSLKGLMGNVICSPAYWKPSTFGGEV
GFQIINTASIQSLICNNVKGCPFTSFSVPDPELIKTVTINASSSRSGLDDINPTVLLKER
STEL
Target 1 Number of Residues 614
Target 1 Molecular Weight 68997
Target 1 Theoretical pI 7.41
Target 1 GO Classification
Function
antioxidant activity
peroxidase activity
Process
Not Available
Component
Not Available
Target 1 General Function Involved in peroxidase activity
Target 1 Specific Function May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity
Target 1 Pathways
Name SMPDB Link KEGG Link
Prostaglandin and leukotriene metabolism map00590 Link Image
Target 1 Reactions
  • arachidonate + AH2 + 2 O2 = prostaglandin H2 + A + H2O
Target 1 Pfam Domain Function
Target 1 Signals
  • 1-17
Target 1 Transmembrane Regions
  • None
Target 1 Essentiality Non-Essential
Target 1 GenBank ID Protein 291988 Link Image
Target 1 UniProtKB/Swiss-Prot ID P35354 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name PGH2_HUMAN Link Image
Target 1 PDB ID Not Available
Target 1 Cellular Location
  • Microsome
  • microsomal membrane
  • peripheral membrane protein
Target 1 Gene Sequence >1815 bp 
ATGCTCGCCCGCGCCCTGCTGCTGTGCGCGGTCCTGGCGCTCAGCCATACAGCAAATCCT
TGCTGTTCCCACCCATGTCAAAACCGAGGTGTATGTATGAGTGTGGGATTTGACCAGTAT
AAGTGCGATTGTACCCGGACAGGATTCTATGGAGAAAACTGCTCAACACCGGAATTTTTG
ACAAGAATAAAATTATTTCTGAAACCCACTCCAAACACAGTGCACTACATACTTACCCAC
TTCAAGGGATTTTGGAACGTTGTGAATAACATTCCCTTCCTTCGAAATGCAATTATGAGT
TATGTGTTGACATCCAGATCACATTTGATTGACAGTCCACCAACTTACAATGCTGACTAT
GGCTACAAAAGCTGGGAAGCCTTCTCTAACCTCTCCTATTATACTAGAGCCCTTCCTCCT
GTGCCTGATGATTGCCCGACTCCCTTGGGTGTCAAAGGTAAAAAGCAGCTTCCTGATTCA
AATGAGATTGTGGAAAAATTGCTTCTAAGAAGAAAGTTCATCCCTGATCCCCAGGGCTCA
AACATGATGTTTGCATTCTTTGCCCAGCACTTCACGCATCAGTTTTTCAAGACAGATCAT
AAGCGAGGGCCAGCTTTCACCAACGGGCTGGGCCATGGGGTGGACTTAAATCATATTTAC
GGTGAAACTCTGGCTAGACAGCGTAAACTGCGCCTTTTCAAGGATGGAAAAATGAAATAT
CAGATAATTGATGGAGAGATGTATCCTCCCACAGTCAAAGATACTCAGGCAGAGATGATC
TACCCTCCTCAAGTCCCTGAGCATCTACGGTTTGCTGTGGGGCAGGAGGTCTTTGGTCTG
GTGCCTGGTCTGATGATGTATGCCACAATCTGGCTGCGGGAACACAACAGAGTATGCGAT
GTGCTTAAACAGGAGCATCCTGAATGGGGTGATGAGCAGTTGTTCCAGACAAGCAGGCTA
ATACTGATAGGAGAGACTATTAAGATTGTGATTGAAGATTATGTGCAACACTTGAGTGGC
TATCACTTCAAACTGAAATTTGACCCAGAACTACTTTTCAACAAACAATTCCAGTACCAA
AATCGTATTGCTGCTGAATTTAACACCCTCTATCACTGGCATCCCCTTCTGCCTGACACC
TTTCAAATTCATGACCAGAAATACAACTATCAACAGTTTATCTACAACAACTCTATATTG
CTGGAACATGGAATTACCCAGTTTGTTGAATCATTCACCAGGCAAATTGCTGGCAGGGTT
GCTGGTGGTAGGAATGTTCCACCCGCAGTACAGAAAGTATCACAGGCTTCCACTGACCAG
AGCAGGCAGATGAAATACCAGTCTTTTAATGAGTACCGCAAACGCTTTATGCTGAAGCCC
TATGAATCATTTGAAGAACTTACAGGAGAAAAGGAAATGTCTGCAGAGTTGGAAGCACTC
TATGGTGACATCGATGCTGTGGAGCTGTATCCTGCCCTTCTGGTAGAAAAGCCTCGGCCA
GATGCCATCTTTGGTGAAACCATGGTAGAAGTTGGAGCACCATTCTCCTTGAAAGGACTT
ATGGGTAATGTTATATGTTCTCCTGCCTACTGGAAGCCAAGCACTTTTGGTGGAGAAGTG
GGTTTTCAAATCATCAACACTGCCTCAATTCAGTCTCTCATCTGCAATAACGTGAAGGGC
TGTCCCTTTACTTCATTCAGTGTTCCAGATCCAGAGCTCATTAAAACAGTCACCATCAAT
GCAAGTTCTTCCCGCTCCGGACTAGATGATATCAATCCCACAGTACTACTAAAAGAACGT
TCGACTGAACTGTAG
Target 1 GenBank Gene ID
Target 1 GeneCard ID PTGS2 Link Image
Target 1 GenAtlas ID PTGS2 Link Image
Target 1 HGNC ID HGNC:9605 Link Image
Target 1 Chromosome Location 1
Target 1 Locus 1q25.2-q25.3
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Hla T, Neilson K: Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384-8. [PubMed Link Image]
  2. Appleby SB, Ristimaki A, Neilson K, Narko K, Hla T: Structure of the human cyclo-oxygenase-2 gene. Biochem J. 1994 Sep 15;302 ( Pt 3):723-7. [PubMed Link Image]
  3. Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T: Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem. 1994 May 1;221(3):889-97. [PubMed Link Image]
  4. Jones DA, Carlton DP, McIntyre TM, Zimmerman GA, Prescott SM: Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem. 1993 Apr 25;268(12):9049-54. [PubMed Link Image]
Target 1 Drug References
  1. Horrobin DF: A low toxicity maintenance regime, using eicosapentaenoic acid and readily available drugs, for mantle cell lymphoma and other malignancies with excess cyclin D1 levels. Med Hypotheses. 2003 May;60(5):615-23. [PubMed Link Image]
  2. Hada M, Mizutari K: [A case report of metastatic pancreatic cancer that responded remarkably to the combination of thalidomide, celecoxib and irinotecan] Gan To Kagaku Ryoho. 2004 Sep;31(9):1407-10. [PubMed Link Image]
  3. Payvandi F, Wu L, Haley M, Schafer PH, Zhang LH, Chen RS, Muller GW, Stirling DI: Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. Cell Immunol. 2004 Aug;230(2):81-8. [PubMed Link Image]
  4. Wiedmann MW, Caca K: Molecularly targeted therapy for gastrointestinal cancer. Curr Cancer Drug Targets. 2005 May;5(3):171-93. [PubMed Link Image]
  5. Du GJ, Lin HH, Xu QT, Wang MW: Thalidomide inhibits growth of tumors through COX-2 degradation independent of antiangiogenesis. Vascul Pharmacol. 2005 Aug;43(2):112-9. [PubMed Link Image]
Drug Target 2 [top]
Target 2 ID 777
Target 2 Name Tumor necrosis factor
Target 2 Synonyms
  1. Cachectin
  2. TNF-a
  3. TNF-alpha
  4. Tumor necrosis factor ligand superfamily member 2
  5. Tumor necrosis factor precursor
Target 2 Gene Name TNF
Target 2 Protein Sequence >Tumor necrosis factor precursor 
MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGVIGPQR
EEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELR
DNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRE
TPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL
Target 2 Number of Residues 236
Target 2 Molecular Weight 25645
Target 2 Theoretical pI 6.92
Target 2 GO Classification
Function
signal transducer activity
receptor binding
cytokine activity
tumor necrosis factor receptor binding
Process
response to stimulus
response to biotic stimulus
defense response
immune response
Component
cell
membrane
Target 2 General Function Involved in tumor necrosis factor receptor binding
Target 2 Specific Function Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin 1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation
Target 2 Pathways Not Available
Target 2 Reactions Not Available
Target 2 Pfam Domain Function
Target 2 Signals
  • None
Target 2 Transmembrane Regions
  • 36-56
Target 2 Essentiality Non-Essential
Target 2 GenBank ID Protein 339741 Link Image
Target 2 UniProtKB/Swiss-Prot ID P01375 Link Image
Target 2 UniProtKB/Swiss-Prot Entry Name TNFA_HUMAN Link Image
Target 2 PDB ID 1A8M Link Image
Target 2 PDB File Show
Target 2 3D Structure
Target 2 Cellular Location
  • Cell membrane
  • single-pass type II membrane protein. Processed form:Secreted protein. Also exists as
Target 2 Gene Sequence >702 bp 
ATGAGCACTGAAAGCATGATCCGGGACGTGGAGCTGGCCGAGGAGGCGCTCCCCAAGAAG
ACAGGGGGGCCCCAGGGCTCCAGGCGGTGCTTGTTCCTCAGCCTCTTCTCCTTCCTGATC
GTGGCAGGCGCCACCACGCTCTTCTGCCTGCTGCACTTTGGAGTGATCGGCCCCCAGAGG
GAAGAGTTCCCCAGGGACCTCTCTCTAATCAGCCCTCTGGCCCAGGCAGTCAGATCATCT
TCTCGAACCCCGAGTGACAAGCCTGTAGCCCATGTTGTAGCAAACCCTCAAGCTGAGGGG
CAGCTCCAGTGGCTGAACCGCCGGGCCAATGCCCTCCTGGCCAATGGCGTGGAGCTGAGA
GATAACCAGCTGGTGGTGCCATCAGAGGGCCTGTACCTCATCTACTCCCAGGTCCTCTTC
AAGGGCCAAGGCTGCCCCTCCACCCATGTGCTCCTCACCCACACCATCAGCCGCATCGCC
GTCTCCTACCAGACCAAGGTCAACCTCCTCTCTGCCATCAAGAGCCCCTGCCAGAGGGAG
ACCCCAGAGGGGGCTGAGGCCAAGCCCTGGTATGAGCCCATCTATCTGGGAGGGGTCTTC
CAGCTGGAGAAGGGTGACCGACTCAGCGCTGAGATCAATCGGCCCGACTATCTCGACTTT
GCCGAGTCTGGGCAGGTCTACTTTGGGATCATTGCCCTGTGA
Target 2 GenBank Gene ID
Target 2 GeneCard ID TNF Link Image
Target 2 GenAtlas ID TNF Link Image
Target 2 HGNC ID HGNC:11892 Link Image
Target 2 Chromosome Location 6
Target 2 Locus 6p21.3
Target 2 SNPs SNPJam Report Link Image
Target 2 General References
  1. Neville MJ, Campbell RD: A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC. J Immunol. 1999 Apr 15;162(8):4745-54. [PubMed Link Image]
  2. Watts AD, Hunt NH, Wanigasekara Y, Bloomfield G, Wallach D, Roufogalis BD, Chaudhri G: A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in 'reverse signalling'. EMBO J. 1999 Apr 15;18(8):2119-26. [PubMed Link Image]
  3. Stevenson FT, Bursten SL, Locksley RM, Lovett DH: Myristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues. J Exp Med. 1992 Oct 1;176(4):1053-62. [PubMed Link Image]
  4. Jones EY, Stuart DI, Walker NP: The structure of tumour necrosis factor--implications for biological function. J Cell Sci Suppl. 1990;13:11-8. [PubMed Link Image]
  5. Van Ostade X, Tavernier J, Prange T, Fiers W: Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis. EMBO J. 1991 Apr;10(4):827-36. [PubMed Link Image]
  6. Eck MJ, Sprang SR: The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding. J Biol Chem. 1989 Oct 15;264(29):17595-605. [PubMed Link Image]
  7. Jones EY, Stuart DI, Walker NP: Structure of tumour necrosis factor. Nature. 1989 Mar 16;338(6212):225-8. [PubMed Link Image]
  8. Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW: Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985 Sep 11;13(17):6361-73. [PubMed Link Image]
  9. Nedospasov SA, Shakhov AN, Turetskaya RL, Mett VA, Azizov MM, Georgiev GP, Korobko VG, Dobrynin VN, Filippov SA, Bystrov NS, et al.: Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) in the human genome. Cold Spring Harb Symp Quant Biol. 1986;51 Pt 1:611-24. [PubMed Link Image]
  10. Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF: Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149-54. [PubMed Link Image]
  11. 3883195 Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB: Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. Nature. 1985 Feb 28-Mar 6;313(6005):803-6.
  12. 3932069 Marmenout A, Fransen L, Tavernier J, Van der Heyden J, Tizard R, Kawashima E, Shaw A, Johnson MJ, Semon D, Muller R, et al.: Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor. Eur J Biochem. 1985 Nov 4;152(3):515-22.
  13. 6392892 Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV: Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20-1985 Jan 2;312(5996):724-9.
  14. 8499947 Iris FJ, Bougueleret L, Prieur S, Caterina D, Primas G, Perrot V, Jurka J, Rodriguez-Tome P, Claverie JM, Dausset J, et al.: Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment. Nat Genet. 1993 Feb;3(2):137-45.
  15. 8597870 Pocsik E, Duda E, Wallach D: Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in transfected HeLa cells. J Inflamm. 1995;45(3):152-60.
  16. 9034191 Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD, et al.: Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature. 1997 Feb 20;385(6618):733-6.
  17. 9442056 Cha SS, Kim JS, Cho HS, Shin NK, Jeong W, Shin HC, Kim YJ, Hahn JH, Oh BH: High resolution crystal structure of a human tumor necrosis factor-alpha mutant with low systemic toxicity. J Biol Chem. 1998 Jan 23;273(4):2153-60.
  18. 9488135 Reed C, Fu ZQ, Wu J, Xue YN, Harrison RW, Chen MJ, Weber IT: Crystal structure of TNF-alpha mutant R31D with greater affinity for receptor R1 compared with R2. Protein Eng. 1997 Oct;10(10):1101-7.
Target 2 Drug References
  1. Richardson P, Hideshima T, Anderson K: Thalidomide in multiple myeloma. Biomed Pharmacother. 2002 May;56(3):115-28. [PubMed Link Image]
  2. Fu LM, Fu-Liu CS: Thalidomide and tuberculosis. Int J Tuberc Lung Dis. 2002 Jul;6(7):569-72. [PubMed Link Image]
  3. Enomoto N, Takei Y, Hirose M, Ikejima K, Miwa H, Kitamura T, Sato N: Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-alpha production. Gastroenterology. 2002 Jul;123(1):291-300. [PubMed Link Image]
  4. Rajkumar SV: Thalidomide in the treatment of multiple myeloma. Expert Rev Anticancer Ther. 2001 Jun;1(1):20-8. [PubMed Link Image]
  5. Vescovo G, Ravara B, Angelini A, Sandri M, Carraro U, Ceconi C, Dalla Libera L: Effect of thalidomide on the skeletal muscle in experimental heart failure. Eur J Heart Fail. 2002 Aug;4(4):455-60. [PubMed Link Image]
Drug Target 3 [top]
Target 3 ID 1787
Target 3 Name Nuclear factor NF-kappa-B p105 subunit
Target 3 Synonyms
  1. DNA-binding factor KBF1
  2. EBP- 1
Target 3 Gene Name NFKB1
Target 3 Protein Sequence >Nuclear factor NF-kappa-B p105 subunit 
MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYV
CEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCED
GICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQA
EGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIY
DSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDF
SPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQ
RKRQKLMPNFSDSFGGGSGAGAGGGGMFGSGGGGGGTGSTGPGYSFPHYGFPTYGGITFH
PGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGE
VTLTYATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQD
ENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVED
LLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMM
SNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGT
TPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMAT
SWQVFDILNGKPYEPEFTSDDLLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLG
LGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQ
AHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQ
EGPLEGKI
Target 3 Number of Residues 984
Target 3 Molecular Weight 105357
Target 3 Theoretical pI 5.05
Target 3 GO Classification
Function
nucleic acid binding
DNA binding
transcription factor activity
binding
protein binding
Process
regulation of biological process
regulation of physiological process
regulation of metabolism
regulation of cellular metabolism
regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism
regulation of transcription
regulation of transcription, DNA-dependent
cellular process
cell communication
signal transduction
Component
organelle
membrane-bound organelle
intracellular membrane-bound organelle
nucleus
Target 3 General Function Involved in transcription factor activity
Target 3 Specific Function Appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur posttranslationally. p50 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. Plays a role in the regulation of apoptosis
Target 3 Pathways Not Available
Target 3 Reactions Not Available
Target 3 Pfam Domain Function
Target 3 Signals
  • None
Target 3 Transmembrane Regions
  • None
Target 3 Essentiality Non-Essential
Target 3 GenBank ID Protein 189180 Link Image
Target 3 UniProtKB/Swiss-Prot ID P19838 Link Image
Target 3 UniProtKB/Swiss-Prot Entry Name NFKB1_HUMAN Link Image
Target 3 PDB ID 1SVC Link Image
Target 3 PDB File Show
Target 3 3D Structure
Target 3 Cellular Location
  • Nucleus. Cytoplasm. Note=Nuclear, but also found in the cytoplasm in an inactive form complexed to a
Target 3 Gene Sequence >2910 bp 
ATGGCAGAAGATGATCCATATTTGGGAAGGCCTGAACAAATGTTTCATTTGGATCCTTCT
TTGACTCATACAATATTTAATCCAGAAGTATTTCAACCACAGATGGCACTGCCAACAGCA
GATGGCCCATACCTTCAAATATTAGAGCAACCTAAACAGAGAGGATTTCGTTTCCGTTAT
GTATGTGAAGGCCCATCCCATGGTGGACTACCTGGTGCCTCTAGTGAAAAGAACAAGAAG
TCTTACCCTCAGGTCAAAATCTGCAACTATGTGGGACCAGCAAAGGTTATTGTTCAGTTG
GTCACAAATGGAAAAAATATCCACCTGCATGCCCACAGCCTGGTGGGAAAACACTGTGAG
GATGGGATCTGCACTGTAACTGCTGGACCCAAGGACATGGTGGTCGGCTTCGCAAACCTG
GGTATACTTCATGTGACAAAGAAAAAAGTATTTGAAACACTGGAAGCACGAATGACAGAG
GCGTGTATAAGGGGCTATAATCCTGGACTCTTGGTGCACCCTGACCTTGCCTATTTGCAA
GCAGAAGGTGGAGGGGACCGGCAGCTGGGAGATCGGGAAAAAGAGCTAATCCGCCAAGCA
GCTCTGCAGCAGACCAAGGAGATGGACCTCAGCGTGGTGCGGCTCATGTTTACAGCTTTT
CTTCCGGATAGCACTGGCAGCTTCACAAGGCGCCTGGAACCCGTGGTATCAGACGCCATC
TATGACAGTAAAGCCCCCAATGCATCCAACTTGAAAATTGTAAGAATGGACAGGACAGCT
GGATGTGTGACTGGAGGGGAGGAAATTTATCTTCTTTGTGACAAAGTTCAGAAAGATGAC
ATCCAGATTCGATTTTATGAAGAGGAAGAAAATGGTGGAGTCTGGGAAGGATTTGGAGAT
TTTTCCCCCACAGATGTTCATAGACAATTTGCCATTGTCTTCAAAACTCCAAAGTATAAA
GATATTAATATTACAAAACCAGCCTCTGTGTTTGTCCAGCTTCGGAGGAAATCTGACTTG
GAAACTAGTGAACCAAAACCTTTCCTCTACTATCCTGAAATCAAAGATAAAGAAGAAGTG
CAGAGGAAACGTCAGAAGCTCATGCCCAATTTTTCGGATAGTTTCGGCGGTGGTAGTGGT
GCCGGAGCTGGAGGCGGAGGCATGTTTGGTAGTGGCGGTGGAGGAGGGGGCACTGGAAGT
ACAGGTCCAGGGTATAGCTTCCCACACTATGGATTTCCTACTTATGGTGGGATTACTTTC
CATCCTGGAACTACTAAATCTAATGCTGGGATGAAGCATGGAACCATGGACACTGAATCT
AAAAAGGACCCTGAAGGTTGTGACAAAAGTGATGACAAAAACACTGTAAACCTCTTTGGG
AAAGTTATTGAAACCACAGAGCAAGATCAGGAGCCCAGCGAGGCCACCGTTGGGAATGGT
GAGGTCACTCTAACGTATGCAACAGGAACAAAAGAAGAGAGTGCTGGAGTTCAGGATAAC
CTCTTTCTAGAGAAGGCTATGCAGCTTGCAAAGAGGCATGCCAATGCCCTTTTCGACTAC
GCGGTGACAGGAGACGTGAAGATGCTGCTGGCCGTCCAGCGCCATCTCACTGCTGTGCAG
GATGAGAATGGGGACAGTGTCTTACACTTAGCAATCATCCACCTTCATTCTCAACTTGTG
AGGGATCTACTAGAAGTCACATCTGGTTTGATTTCTGATGACATTATCAACATGAGAAAT
GATCTGTACCAGACGCCCTTGCACTTGGCAGTGATCACTAAGCAGGAAGATGTGGTGGAG
GATTTGCTGAGGGCTGGGGCCGACCTGAGCCTTCTGGACCGCTTGGGTAACTCTGTTTTG
CACCTAGCTGCCAAAGAAGGACATGATAAAGTTCTCAGTATCTTACTCAAGCACAAAAAG
GCAGCACTACTTCTTGACCACCCCAACGGGGACGGTCTGAATGCCATTCATCTAGCCATG
ATGAGCAATAGCCTGCCATGTTTGCTGCTGCTGGTGGCCGCTGGGGCTGACGTCAATGCT
CAGGAGCAGAAGTCCGGGCGCACAGCACTGCACCTGGCTGTGGAGCACGACAACATCTCA
TTGGCAGGCTGCCTGCTCCTGGAGGGTGATGCCCATGTGGACAGTACTACCTACGATGGA
ACCACACCCCTGCATATAGCAGCTGGGAGAGGGTCCACCAGGCTGGCAGCTCTTCTCAAA
GCAGCAGGAGCAGATCCCCTGGTGGAGAACTTTGAGCCTCTCTATGACCTGGATGACTCT
TGGGAAAATGCAGGAGAGGATGAAGGAGTTGTGCCTGGAACCACGCCTCTAGATATGGCC
ACCAGCTGGCAGGTATTTGACATATTAAATGGGAAACCATATGAGCCAGAGTTTACATCT
GATGATTTACTAGCACAAGGAGACATGAAACAGCTGGCTGAAGATGTGAAGCTGCAGCTG
TATAAGTTACTAGAAATTCCTGATCCAGACAAAAACTGGGCTACTCTGGCGCAGAAATTA
GGTCTGGGGATACTTAATAATGCCTTCCGGCTGAGTCCTGCTCCTTCCAAAACACTTATG
GACAACTATGAGGTCTCTGGGGGTACAGTCAGAGAGCTGGTGGAGGCCCTGAGACAAATG
GGCTACACCGAAGCAATTGAAGTGATCCAGGCAGCCTCCAGCCCAGTGAAGACCACCTCT
CAGGCCCACTCGCTGCCTCTCTCGCCTGCCTCCACAAGGCAGCAAATAGACGAGCTCCGA
GACAGTGACAGTGTCTGCGACACGGGCGTGGAGACATCCTTCCGCAAACTCAGCTTTACC
GAGTCTCTGACCAGTGGTGCCTCACTGCTAACTCTCAACAAAATGCCCCATGATTATGGG
CAGGAAGGACCTCTAGAAGGCAAAATTTAG
Target 3 GenBank Gene ID
Target 3 GeneCard ID NFKB1 Link Image
Target 3 GenAtlas ID NFKB1 Link Image
Target 3 HGNC ID HGNC:7794 Link Image
Target 3 Chromosome Location 4
Target 3 Locus 4q24
Target 3 SNPs SNPJam Report Link Image
Target 3 General References
  1. Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C: NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of Bcl-3-p50 complexes. EMBO J. 1999 Sep 1;18(17):4766-78. [PubMed Link Image]
  2. Lin L, DeMartino GN, Greene WC: Cotranslational dimerization of the Rel homology domain of NF-kappaB1 generates p50-p105 heterodimers and is required for effective p50 production. EMBO J. 2000 Sep 1;19(17):4712-22. [PubMed Link Image]
  3. Werbajh S, Nojek I, Lanz R, Costas MA: RAC-3 is a NF-kappa B coactivator. FEBS Lett. 2000 Nov 24;485(2-3):195-9. [PubMed Link Image]
  4. Salmeron A, Janzen J, Soneji Y, Bump N, Kamens J, Allen H, Ley SC: Direct phosphorylation of NF-kappaB1 p105 by the IkappaB kinase complex on serine 927 is essential for signal-induced p105 proteolysis. J Biol Chem. 2001 Jun 22;276(25):22215-22. Epub 2001 Apr 10. [PubMed Link Image]
  5. Ayroldi E, Migliorati G, Bruscoli S, Marchetti C, Zollo O, Cannarile L, D'Adamio F, Riccardi C: Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood. 2001 Aug 1;98(3):743-53. [PubMed Link Image]
  6. Berrebi D, Bruscoli S, Cohen N, Foussat A, Migliorati G, Bouchet-Delbos L, Maillot MC, Portier A, Couderc J, Galanaud P, Peuchmaur M, Riccardi C, Emilie D: Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10. Blood. 2003 Jan 15;101(2):729-38. Epub 2002 Sep 12. [PubMed Link Image]
  7. Meyer R, Hatada EN, Hohmann HP, Haiker M, Bartsch C, Rothlisberger U, Lahm HW, Schlaeger EJ, van Loon AP, Scheidereit C: Cloning of the DNA-binding subunit of human nuclear factor kappa B: the level of its mRNA is strongly regulated by phorbol ester or tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):966-70. [PubMed Link Image]
  8. Kieran M, Blank V, Logeat F, Vandekerckhove J, Lottspeich F, Le Bail O, Urban MB, Kourilsky P, Baeuerle PA, Israel A: The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell. 1990 Sep 7;62(5):1007-18. [PubMed Link Image]
  9. Bours V, Villalobos J, Burd PR, Kelly K, Siebenlist U: Cloning of a mitogen-inducible gene encoding a kappa B DNA-binding protein with homology to the rel oncogene and to cell-cycle motifs. Nature. 1990 Nov 1;348(6296):76-80. [PubMed Link Image]
  10. Muller CW, Rey FA, Sodeoka M, Verdine GL, Harrison SC: Structure of the NF-kappa B p50 homodimer bound to DNA. Nature. 1995 Jan 26;373(6512):311-7. [PubMed Link Image]
  11. 8087845 Palombella VJ, Rando OJ, Goldberg AL, Maniatis T: The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773-85.
  12. 8628291 Lin L, Ghosh S: A glycine-rich region in NF-kappaB p105 functions as a processing signal for the generation of the p50 subunit. Mol Cell Biol. 1996 May;16(5):2248-54.
  13. 8825636 Heron E, Deloukas P, van Loon AP: The complete exon-intron structure of the 156-kb human gene NFKB1, which encodes the p105 and p50 proteins of transcription factors NF-kappa B and I kappa B-gamma: implications for NF-kappa B-mediated signal transduction. Genomics. 1995 Dec 10;30(3):493-505.
  14. 9529257 Lin L, DeMartino GN, Greene WC: Cotranslational biogenesis of NF-kappaB p50 by the 26S proteasome. Cell. 1998 Mar 20;92(6):819-28.
  15. 9865693 Jacobs MD, Harrison SC: Structure of an IkappaBalpha/NF-kappaB complex. Cell. 1998 Dec 11;95(6):749-58.
  16. 9950430 Belich MP, Salmeron A, Johnston LH, Ley SC: TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. Nature. 1999 Jan 28;397(6717):363-8.
Target 3 Drug References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed Link Image]
  2. Yasui K, Kobayashi N, Yamazaki T, Agematsu K: Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. Curr Pharm Des. 2005;11(3):395-401. [PubMed Link Image]

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.