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Identification
Name Decitabine
Accession Number DB01262
Type small molecule
Groups approved
Description

Decitabine is indicated for treatment of patients with myelodysplastic syndrome (MDS). It is a chemical analogue of cytidine, a nucleoside present in DNA and RNA. Cells in the presence of Decitabine incorporate it into DNA during replication and RNA during transcription. The incorporation of Decitabine into DNA or RNA inhibits methyltransferase thereby causing demethylation in that sequence. This adversely affects the way that cell regulatory proteins are able to bind to the DNA/RNA substrate.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
5-aza-2'-deoxycytidine
Azadc
Dezocitidine
Salts Not Available
Brand names
Name Company
Dacogen
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Teratogens
  • Antimetabolites, Antineoplastic
CAS number 2353-33-5
Weight Average: 228.2053
Monoisotopic: 228.085854892
Chemical Formula C8H12N4O4
InChI Key InChIKey=XAUDJQYHKZQPEU-KVQBGUIXSA-N
InChI
InChI=1S/C8H12N4O4/c9-7-10-3-12(8(15)11-7)6-1-4(14)5(2-13)16-6/h3-6,13-14H,1-2H2,(H2,9,11,15)/t4-,5+,6+/m0/s1
Plain Text
IUPAC Name
4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one
SMILES
NC1=NC(=O)N(C=N1)[C@H]1C[C@H](O)[C@@H](CO)O1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Glycerol and Derivatives
  • Triazines
Substructures
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Aliphatic and Aryl Amines
  • Ethers
  • Alcohols and Polyols
  • Heterocyclic compounds
  • Aromatic compounds
  • Triazines
  • Furans
  • Cyanamides
Pharmacology
Indication For treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups (scores ≥0.5).
Pharmacodynamics Decitabine is an analogue of the natural nucleoside 2’-deoxycytidine. It functions in the same way as 5-Azacytidine. The antineoplastic activity of this drug is dependent on its intracellular conversion to its 5'-triphosphate metabolite.
Mechanism of action Decitabine is believed to exert its antineoplastic effects following its conversion to decitabine triphosphate, where the drug directly incorporates into DNA and inhibits DNA methyltransferase, the enzyme that is responsible for methylating newly synthesized DNA in mammalian cells. This results in hypomethylation of DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine that has been incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine. Decitabine is cell cycle specific and acts peripherally in the S phase of the cell cycle. It does not inhibit the progression of cells from the G1 to S phase.
Absorption Not Available
Volume of distribution Not Available
Protein binding Plasma protein binding of decitabine is negligible (<1%).
Metabolism The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in the liver but also in granulocytes, intestinal epithelium and whole blood.
Route of elimination Not Available
Half life The terminal phase elimination half-life is 0.51 ± 0.31 hours.
Clearance
  • 125 L/h/m2 [Patients receiving 15 mg/m2 3-hr infusion every 8 hours for 3 days]
  • 210 L/h/m2 [20 mg/m2 1-hr infusion daily for 5 days]
Toxicity There is no known antidote for overdosage with decitabine. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Eisai inc
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Dacogen 50 mg vial 1706.4 USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
water solubility Sparingly soluble Not Available
Predicted Properties
Property Value Source
water solubility 5.50e+00 g/l ALOGPS
logP -2 ALOGPS
logP -2.2 ChemAxon
logS -1.6 ALOGPS
pKa (strongest acidic) 13.89 ChemAxon
pKa (strongest basic) -0.25 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 7 ChemAxon
hydrogen donor count 3 ChemAxon
polar surface area 120.74 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 50.68 ChemAxon
polarizability 21.15 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. Pubmed
  2. Wijermans PW, Ruter B, Baer MR, Slack JL, Hussain SI, Lubbert M: Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Leuk Res. 2007 Sep 17;. Pubmed
  3. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. Pubmed
  4. Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. Pubmed
  5. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. Pubmed
  6. Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. Pubmed
  7. Oki Y, Aoki E, Issa JP: Decitabine—bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. Pubmed
External Links
Resource Link
KEGG Drug D03665 Link_out
PubChem Compound 451668 Link_out
PubChem Substance 46505657 Link_out
ChemSpider 397844 Link_out
ChEBI 50131 Link_out
ChEMBL 50131 Link_out
Therapeutic Targets Database DAP000641 Link_out
PharmGKB PA164749631 Link_out
Drugs.com http://www.drugs.com/cdi/decitabine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Decitabine Link_out
ATC Codes Not Available
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (100 KB)
MSDS Not Available
Interactions
Drug Interactions Searched, but no interactions found.
Food Interactions Not Available
Targets

1. DNA

Pharmacological action: yes
Actions: other/unknown

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. Pubmed
  4. Claus R, Ruter B, Lubbert M: Targets of epigenetic therapy – Gene reactivation as a novel approach in MDS treatment. Cancer Treat Rev. 2007 Sep 27. doi:10.1016/j.ctrv.2007.07.009
  5. Atallah E, Kantarjian H, Garcia-Manero G: The role of decitabine in the treatment of myelodysplastic syndromes. Expert Opin Pharmacother. 2007 Jan;8(1):65-73. Pubmed
  6. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. Pubmed
  7. Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. Pubmed
  8. Oki Y, Aoki E, Issa JP: Decitabine—bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. Pubmed

2. DNA (cytosine-5)-methyltransferase 1

Pharmacological action: yes
Actions: inhibitor

Methylates CpG residues. Preferentially methylates hemimethylated DNA. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2

Organism class: human
UniProt ID: P26358 Link_out
Gene: DNMT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ando T, Nishimura M, Oka Y: Decitabine (5-Aza-2’-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells. Leukemia. 2000 Nov;14(11):1915-20. Pubmed
  2. Karpf AR, Moore BC, Ririe TO, Jones DA: Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2’-deoxycytidine. Mol Pharmacol. 2001 Apr;59(4):751-7. Pubmed
  3. Csankovszki G, Nagy A, Jaenisch R: Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol. 2001 May 14;153(4):773-84. Pubmed
  4. Takebayashi S, Nakao M, Fujita N, Sado T, Tanaka M, Taguchi H, Okumura K: 5-Aza-2’-deoxycytidine induces histone hyperacetylation of mouse centromeric heterochromatin by a mechanism independent of DNA demethylation. Biochem Biophys Res Commun. 2001 Nov 9;288(4):921-6. Pubmed
  5. Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J: Effects of 5-aza-2’-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood. 2003 Dec 1;102(12):3865-70. Epub 2003 Aug 7. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. Pubmed
  8. Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. Pubmed
  9. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. Pubmed
  10. Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. Pubmed
  11. Oki Y, Aoki E, Issa JP: Decitabine—bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. Pubmed
Enzymes

1. Deoxycytidine kinase

Required for the phosphorylation of several deoxyribonucleosides and certain nucleoside analogs widely employed as antiviral and chemotherapeutic agents

UniProt ID: P27707 Link_out
Gene: DCK
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Schwarzenberg J, Radu CG, Benz M, Fueger B, Tran AQ, Phelps ME, Witte ON, Satyamurthy N, Czernin J, Schiepers C: Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway. Eur J Nucl Med Mol Imaging. 2011 Apr;38(4):711-21. Epub 2010 Dec 3. Pubmed
Comments
Drug created on May 16, 2007 11:38 / Updated on February 08, 2013 16:20