DT-Web

DB01262 - Decitabine


Identification
Name Decitabine
Accession Number DB01262
Type small molecule
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
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 228.2053
Groups approved
Monoisotopic Weight 228.085854892
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).
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
Protein binding Plasma protein binding of decitabine is negligible (<1%).
Biotransformation 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
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
Interactions
Drug Interactions Not Available
Food Interactions Not Available

Targets


DNA
Name DNA
Gene Name Not Available
Pharmacological action yes
Actions other/unknown
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
DTHybrid score Not Available
DNA (cytosine-5)-methyltransferase 1
Name DNA (cytosine-5)-methyltransferase 1
Gene Name DNMT1
Pharmacological action yes
Actions inhibitor
References
  • 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
  • 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
  • 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
  • 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
  • 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
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
  • Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. - Pubmed
  • Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. - Pubmed
  • 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
  • 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
  • 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
DTHybrid score 0.7124

Enzymes


Deoxycytidine kinase
Name Deoxycytidine kinase
Gene Name DCK
Actions Not Available
References
  • -
  • 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
DTHybrid score 0.5744

Predictions


Id Partner name Gene Name Score
24 Thymidylate synthase TMP1 0.2102
359 Thymidylate synthase TYMS 0.2102
2626 Thymidylate synthase thyA 0.2102
2729 Thymidylate synthase thyA 0.2102
5352 Thymidylate synthase THYA 0.2102
3611 Cytidine deaminase cdd 0.1816
3707 Cytidine deaminase cdd 0.1816
4211 Cytidine deaminase CDA 0.1816
603 DNA polymerase alpha catalytic subunit POLA1 0.1062
3690 Class B acid phosphatase precursor aphA 0.0952
360 Ribonucleoside-diphosphate reductase large subunit RRM1 0.0796
2222 Equilibrative nucleoside transporter 1 SLC29A1 0.0724
6083 Deoxyguanosine kinase, mitochondrial DGUOK 0.0461
6171 Solute carrier family 28 member 3 SLC28A3 0.0457
6144 Solute carrier family 22 member 2 SLC22A2 0.0336
6145 Solute carrier family 22 member 1 SLC22A1 0.0323
6147 Solute carrier family 22 member 3 SLC22A3 0.0247
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0231
702 UMP-CMP kinase CMPK1 0.0222
3957 Adenosine deaminase ADA 0.022
1043 Trifunctional purine biosynthetic protein adenosine-3 [Includes: Phosphoribosylamine--glycine ligase GART 0.0205
833 Organic cation/carnitine transporter 1 SLC22A4 0.02
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0199
6148 Multidrug resistance-associated protein 7 ABCC10 0.0194
2287 Bifunctional purine biosynthesis protein PURH [Includes: Phosphoribosylaminoimidazolecarboxamide formyltransferase ATIC 0.0176
118 Organic cation/carnitine transporter 2 SLC22A5 0.0175
3923 Cholinesterase BCHE 0.0171
4119 Cytochrome P450 2D6 CYP2D6 0.017
1830 5'-nucleotidase NT5E 0.0163
125 DNA polymerase beta POLB 0.0153
6111 DNA polymerase epsilon subunit 4 POLE4 0.0131
6112 DNA polymerase epsilon subunit 3 POLE3 0.0131
6108 Ribonucleoside-diphosphate reductase subunit M2 B RRM2B 0.0131
6110 DNA polymerase epsilon subunit 2 POLE2 0.0131
6109 DNA polymerase epsilon catalytic subunit A POLE 0.0131
365 Dihydrofolate reductase DHFR 0.0131
2381 Dihydrofolate reductase DFR1 0.0131
2833 Dihydrofolate reductase Not Available 0.0131
2931 Dihydrofolate reductase folA 0.0131
3544 Dihydrofolate reductase folA 0.0131
3682 Dihydrofolate reductase folA 0.0131
6642 Dihydrofolate reductase folA 0.0131
6756 Dihydrofolate reductase dfrA 0.0131
4218 Ribonucleoside-diphosphate reductase M2 subunit RRM2 0.0102
342 P protein [Includes: DNA-directed DNA polymerase P 0.0099
612 P protein [Includes: DNA-directed DNA polymerase P 0.0099
1729 Solute carrier family 22 member 6 SLC22A6 0.0093
6031 Cytochrome P450 3A43 CYP3A43 0.0091
677 Choline-phosphate cytidylyltransferase A PCYT1A 0.0088
4512 Cytochrome P450 3A4 CYP3A4 0.0087
1588 Multidrug resistance protein 1 ABCB1 0.0081
5626 Nucleoside diphosphate kinase B NME2 0.0079
6143 Solute carrier family 22 member 7 SLC22A7 0.0071
5294 Nucleoside diphosphate kinase A NME1 0.007
277 Purine nucleoside phosphorylase PNP 0.0065
2870 Purine nucleoside phosphorylase punA 0.0065
2945 Purine nucleoside phosphorylase punA 0.0065
4659 Purine nucleoside phosphorylase TM_1596 0.0065
4825 Purine nucleoside phosphorylase TTHA1435 0.0065
6107 Cytochrome P450 3A7 CYP3A7 0.0055
4118 Cytochrome P450 3A5 CYP3A5 0.0052
4757 Cytochrome P450 2C9 CYP2C9 0.0047
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0046
2164 Multidrug resistance-associated protein 4 ABCC4 0.0044
862 Multidrug resistance-associated protein 1 ABCC1 0.004
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0038
5287 Signaling protein Not Available 0.0021
5288 Shikimate kinase aroK 0.0021
5304 UPF0166 protein TM_0021 TM_0021 0.0021
5270 ATP-dependent Clp protease ATP-binding subunit clpX clpX 0.0021
5314 UPF0079 ATP-binding protein HI0065 HI_0065 0.0021
5259 Transcriptional regulator ntrC1 0.0021
6699 Transcriptional regulator Cgl2612 0.0021
5290 ATP-dependent hsl protease ATP-binding subunit hslU hslU 0.0021
5638 ATP-dependent hsl protease ATP-binding subunit hslU hslU 0.0021
3199 Phosphopantetheine adenylyltransferase coaD 0.0021
3543 Phosphopantetheine adenylyltransferase coaD 0.0021
3567 Phosphopantetheine adenylyltransferase coaD 0.0021
5289 Phosphopantetheine adenylyltransferase coaD 0.0021
2874 Nitrogenase iron protein 1 nifH1 0.0021
4346 Polynucleotide kinase pseT 0.0021
5293 Shikimate kinase 2 aroL 0.0021
5292 Putative partitioning protein TT_C1605 0.0021
5281 Plasmid segregation protein parM parM 0.0021
5305 Phosphoribosylaminoimidazole carboxylase ATPase subunit purK 0.0021
5299 D-alanine--D-alanine ligase ddl 0.0021
6598 D-alanine--D-alanine ligase ddl 0.0021
5276 Chromosomal replication initiator protein dnaA dnaA 0.0021
5266 Activator of hgdC 0.0021
4794 Phosphoenolpyruvate carboxykinase [ATP] pckA 0.0021
5283 D-alanine--D-alanine ligase B ddlB 0.0021
5275 Multidrug resistance ABC transporter ATP-binding and permease protein lmrA 0.0021
5308 Preprotein translocase secA 1 subunit secA1 0.0021
5315 Chaperone protein htpG htpG 0.0021
1549 Heat shock 70 kDa protein 1 HSPA1A 0.0021
5284 Large T antigen Not Available 0.0021
3777 ATP-dependent Clp protease ATP-binding subunit clpA clpA 0.0021
3982 Phosphoribosylformylglycinamidine synthase PFAS 0.0021
5261 Phosphoribosylformylglycinamidine synthase purL 0.0021
5277 Preprotein translocase subunit secA secA 0.0021
5291 Glycogen synthase 1 glgA1 0.0021
5264 DNA replication protein REP 0.0021
5285 Kinesin heavy chain KIF5B 0.0021
4106 Guanylate kinase GUK1 0.0016
4516 Guanylate kinase gmk 0.0016
413 Amidophosphoribosyltransferase PPAT 0.0016
2515 Amidophosphoribosyltransferase purF 0.0016
3714 Amidophosphoribosyltransferase purF 0.0016
6277 Heat shock cognate 71 kDa protein HSPA8 0.0016
3390 Aminoglycoside 3'-phosphotransferase aphA 0.0016
6029 Aminoglycoside 3'-phosphotransferase aphA1 0.0016
4837 Cag-alfa cag-alfa 0.0016
5646 Galactokinase GALK1 0.0016
5302 TrwB trwB 0.0016
4839 DNA polymerase III subunit tau dnaX 0.0016
4774 NTPase P4 Not Available 0.0016
4838 PMS1 protein homolog 2 PMS2 0.0016
5265 FtsH ftsH 0.0016
340 Apoptotic protease-activating factor 1 APAF1 0.0016
2270 Dephospho-CoA kinase coaE 0.0016
5189 Trimethylamine dehydrogenase tmd 0.0016
2284 Adenylate kinase adk 0.0016
2296 Adenylate kinase adk 0.0016
2311 Adenylate kinase adk 0.0016
2312 Adenylate kinase Not Available 0.0016
5295 2-keto-3-deoxy-gluconate kinase TT_P0036 0.0015
2751 Holliday junction ATP-dependent DNA helicase ruvB ruvB 0.0015
4755 Holliday junction ATP-dependent DNA helicase ruvB ruvB 0.0015
3470 Hypothetical protein MG245 homolog MPN_348 0.0015
3175 Glutamate--cysteine ligase gshA 0.0015
3426 Glutamine synthetase glnA 0.0015
3987 Glutamine synthetase GLUL 0.0015
5300 Antigen peptide transporter 1 TAP1 0.0015
2683 Mono-ADP-ribosyltransferase C3 C3 0.0015
2390 Nonsecretory ribonuclease RNASE2 0.0014
5312 Kinesin-like protein KIF1A KIF1A 0.0014
2282 Protein recA recA 0.0014
2315 Protein recA recA 0.0014
2332 Protein recA recA 0.0014
5263 Protein recA recA 0.0014
2922 Glycerol kinase glpK 0.0014
408 Riboflavin kinase RFK 0.0014
5271 Focal adhesion kinase 1 PTK2 0.0013
2615 Chemotaxis protein cheA cheA 0.0013
5278 Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthetase 1 PAPSS1 0.0013
6832 Serine/threonine-protein kinase SRPK2 SRPK2 0.0013
1881 Hexokinase-1 HK1 0.0013
2371 Pantothenate kinase coaA 0.0013
3669 Ribokinase rbsK 0.0013
2950 Inositol-trisphosphate 3-kinase A ITPKA 0.0012
2892 Acetylglutamate kinase argB 0.0012
3550 Acetylglutamate kinase argB 0.0012
4366 Riboflavin kinase/FMN adenylyltransferase TM_0857 0.0012
825 Arsenical pump-driving ATPase ASNA1 0.0012
3435 Arsenical pump-driving ATPase arsA 0.0012
137 FolC bifunctional protein [Includes: Folylpolyglutamate synthase folC 0.0012
2697 Uridine-cytidine kinase 2 UCK2 0.0012
6857 [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 2, mitochondrial PDK2 0.0012
2727 S-adenosylmethionine synthetase metK 0.0012
201 Glutamate dehydrogenase 1, mitochondrial GLUD1 0.0011
788 Creatine kinase M-type CKM 0.0011
2817 Phosphoribosylglycinamide formyltransferase 2 purT 0.0011
6390 Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 ATP2A1 0.0011
453 S-adenosylmethionine synthetase isoform type-1 MAT1A 0.0011
48 Pyridoxal kinase PDXK 0.0011
2251 Thymidylate kinase tmk 0.0011
2254 Thymidylate kinase DTYMK 0.0011
3522 Thymidylate kinase tmk 0.0011
61 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase folK 0.0011
2644 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase folK 0.0011
2710 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase folK 0.0011
207 Glutathione synthetase GSS 0.001
5269 Glutathione synthetase gshB 0.001
2334 Dethiobiotin synthetase bioD 0.001
6555 Dethiobiotin synthetase bioD 0.001
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.001
2091 Endoplasmin HSP90B1 0.001
2511 MAP kinase-activated protein kinase 2 MAPKAPK2 0.001
2317 UDP-N-acetylmuramoylalanine--D-glutamate ligase murD 0.001
509 Thymidine kinase TK 0.001
570 Thymidine kinase TK 0.001
2559 Thymidine kinase TK 0.001
3430 Thymidine kinase tdk 0.001
3518 Thymidine kinase TK 0.001
5301 Thymidine kinase tdk 0.001
5771 Thymidine kinase ORF36 0.001
7009 Thymidine kinase ORF36 0.001
6395 Myosin-14 MYH14 0.0009
1422 Serine/threonine-protein kinase 6 AURKA 0.0009
504 Mast/stem cell growth factor receptor KIT 0.0009
3379 Kinesin-like protein KIF11 KIF11 0.0009
3456 Heat shock protein HSP 90-beta HSP90AB1 0.0009
3822 Actin, alpha skeletal muscle ACTA1 0.0009
631 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCR 0.0008
3387 3-hydroxy-3-methylglutaryl-coenzyme A reductase mvaA 0.0008
5682 Ribonuclease pancreatic RNASE1 0.0008
1721 Glycogen synthase kinase-3 beta GSK3B 0.0008
1939 Heat shock protein HSP 90-alpha HSP90AA1 0.0007
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