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Identification
NameCladribine
Accession NumberDB00242  (APRD00260)
TypeSmall Molecule
GroupsApproved, Investigational
Description

An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. [PubChem]

Structure
Thumb
Synonyms
(2R,3S,5R)-5-(6-amino-2-Chloropurin-9-yl)-2-(hydroxymethyl)oxolan-3-ol
2-CdA
2-Chloro-2'-deoxy-beta-adenosine
2-Chloro-2'-deoxyadenosine
2-chloro-6-amino-9-(2-Deoxy-beta-D-erythro-pentofuranosyl)purine
2-chloro-Deoxyadenosine
2-Chlorodeoxyadenosine
2ClAdo
Cladribina
Cladribine
Cladribinum
CldAdo
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cladribine Injectionsolution1 mgintravenousFresenius Kabi Canada Ltd2009-06-30Not applicableCanada
Leustatin 1mg/mlsolution1 mgintravenousJanssen Inc1993-12-312011-12-19Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cladribineinjection1 mg/mLintravenousPfizer Laboratories Div Pfizer Inc.2011-07-10Not applicableUs
Cladribineinjection1 mg/mLintravenousMylan Institutional LLC2011-10-07Not applicableUs
Cladribineinjection1 mg/mLintravenousMylan Institutional LLC2011-07-10Not applicableUs
Cladribineinjection1 mg/mLintravenousFresenius Kabi USA, LLC2004-12-01Not applicableUs
Cladribineinjection1 mg/mLintravenousPfizer Laboratories Div Pfizer Inc.2011-10-07Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
LeustatinNot Available
LitakNot Available
MovectroNot Available
MylinaxNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII47M74X9YT5
CAS number4291-63-8
WeightAverage: 285.687
Monoisotopic: 285.062866982
Chemical FormulaC10H12ClN5O3
InChI KeyInChIKey=PTOAARAWEBMLNO-KVQBGUIXSA-N
InChI
InChI=1S/C10H12ClN5O3/c11-10-14-8(12)7-9(15-10)16(3-13-7)6-1-4(18)5(2-17)19-6/h3-6,17-18H,1-2H2,(H2,12,14,15)/t4-,5+,6+/m0/s1
IUPAC Name
(2R,3S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol
SMILES
NC1=C2N=CN([[email protected]]3C[[email protected]](O)[C@@H](CO)O3)C2=NC(Cl)=N1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as purine 3'-deoxyribonucleosides. These are compounds consisting of a purine linked to a ribose which lacks a hydroxyl group at position 3.
KingdomOrganic compounds
Super ClassNucleosides, nucleotides, and analogues
ClassPurine nucleosides
Sub ClassPurine 3'-deoxyribonucleosides
Direct ParentPurine 3'-deoxyribonucleosides
Alternative Parents
Substituents
  • Purine 3'-deoxyribonucleoside
  • Purine 2'-deoxyribonucleoside
  • 6-aminopurine
  • Purine
  • Imidazopyrimidine
  • Halopyrimidine
  • Aminopyrimidine
  • Imidolactam
  • Pyrimidine
  • Primary aromatic amine
  • N-substituted imidazole
  • Saccharide
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Oxolane
  • Imidazole
  • Azole
  • Secondary alcohol
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Primary amine
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.
PharmacodynamicsCladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites. Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply.
Mechanism of actionCladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. Although the exact mechanism of action has not been fully determined, evidence shows that cladribine is phosphorylated by deoxycytidine kinase to the nucleotidecladribine triphosphate (CdATP; 2-chloro-2′-deoxyadenosine 5′-triphosphate), which accumulates and is incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine kinase and low levels of deoxynucleotidase, resulting in DNA strand breakage and inhibition of DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase (PNP), however no relationship between this binding and a mechanism of action has been established.
Related Articles
AbsorptionOral bioavailability is 34 to 48%.
Volume of distribution
  • 4.5 ± 2.8 L/kg [patients with hematologic malignancies]
  • 9 L/kg
Protein binding20%
Metabolism

Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate

SubstrateEnzymesProduct
Cladribine
Not Available
2-chloro-2'-deoxyadenosine-5'-triphosphateDetails
Route of eliminationNot Available
Half life5.4 hours
Clearance
  • 978 +/- 422 mL/h/kg
ToxicitySymptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9386
Caco-2 permeable-0.7394
P-glycoprotein substrateNon-substrate0.6469
P-glycoprotein inhibitor INon-inhibitor0.9139
P-glycoprotein inhibitor IINon-inhibitor0.8526
Renal organic cation transporterNon-inhibitor0.8722
CYP450 2C9 substrateNon-substrate0.8948
CYP450 2D6 substrateNon-substrate0.8145
CYP450 3A4 substrateNon-substrate0.5
CYP450 1A2 substrateNon-inhibitor0.7226
CYP450 2C9 inhibitorNon-inhibitor0.8803
CYP450 2D6 inhibitorNon-inhibitor0.9007
CYP450 2C19 inhibitorNon-inhibitor0.8856
CYP450 3A4 inhibitorNon-inhibitor0.831
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8761
Ames testNon AMES toxic0.8673
CarcinogenicityNon-carcinogens0.6795
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.2055 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9326
hERG inhibition (predictor II)Non-inhibitor0.8344
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • App pharmaceuticals llc
  • Bedford laboratories div ben venue laboratories inc
  • Ortho biotech products lp
Packagers
Dosage forms
FormRouteStrength
Injectionintravenous1 mg/mL
Solutionintravenous1 mg
Prices
Unit descriptionCostUnit
Leustatin 10 mg/10 ml vial102.78USD ml
Cladribine 10 mg/10 ml vial34.2USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point215 °CNot Available
logP-0.1Not Available
Predicted Properties
PropertyValueSource
Water Solubility6.35 mg/mLALOGPS
logP-0.12ALOGPS
logP-0.28ChemAxon
logS-1.6ALOGPS
pKa (Strongest Acidic)13.89ChemAxon
pKa (Strongest Basic)1.33ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area119.31 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity67.18 m3·mol-1ChemAxon
Polarizability25.93 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

Szepsel Gerszberg, “Method for the production of 2-chloro-2' -deoxyadenosine (cladribine) and its 3,5-di-O-p-toluoyl derivative.” U.S. Patent US20020052491, issued May 02, 2002.

US20020052491
General References
  1. Warnke C, Wiendl H, Hartung HP, Stuve O, Kieseier BC: Identification of targets and new developments in the treatment of multiple sclerosis--focus on cladribine. Drug Des Devel Ther. 2010 Jul 21;4:117-26. [PubMed:20689698 ]
  2. Sigal DS, Miller HJ, Schram ED, Saven A: Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood. 2010 Oct 21;116(16):2884-96. doi: 10.1182/blood-2010-02-246140. Epub 2010 Jul 15. [PubMed:20634380 ]
  3. Khalid BA, Hamilton NT, Cauchi MN: Binding of thyroid microsomes by lymphocytes from patients with thyroid disease and normal subjects. Clin Exp Immunol. 1976 Jan;23(1):28-32. [PubMed:1261088 ]
  4. Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. doi: 10.1517/13543780903173222. [PubMed:19715446 ]
  5. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. [PubMed:17852710 ]
  6. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
  7. Larson ML, Venugopal P: Clofarabine: a new treatment option for patients with acute myeloid leukemia. Expert Opin Pharmacother. 2009 Jun;10(8):1353-7. doi: 10.1517/14656560902997990. [PubMed:19463072 ]
External Links
ATC CodesL01BB04
AHFS Codes
  • 10:00.00
PDB Entries
FDA labelNot Available
MSDSDownload (43.7 KB)
Interactions
Drug Interactions
Drug
ClozapineThe risk or severity of adverse effects can be increased when Cladribine is combined with Clozapine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Cladribine.
LeflunomideThe risk or severity of adverse effects can be increased when Cladribine is combined with Leflunomide.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Cladribine.
NatalizumabThe risk or severity of adverse effects can be increased when Cladribine is combined with Natalizumab.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Cladribine.
RoflumilastRoflumilast may increase the immunosuppressive activities of Cladribine.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Cladribine.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Cladribine.
TofacitinibCladribine may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Cladribine.
Food Interactions
  • Echinacea should be used with caution, if at all, in patients receiving therapeutic immunosuppressants. Monitor for reduced efficacy of the immunosuppressant during concomitant use.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor
Specific Function:
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.
Gene Name:
RRM1
Uniprot ID:
P23921
Molecular Weight:
90069.375 Da
References
  1. Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. doi: 10.1517/13543780903173222. [PubMed:19715446 ]
  2. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. [PubMed:17852710 ]
  3. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
  4. Kline JP, Larson RA: Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review. Expert Opin Pharmacother. 2005 Dec;6(15):2711-8. [PubMed:16316309 ]
  5. Takahashi T, Kanazawa J, Akinaga S, Tamaoki T, Okabe M: Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration. Cancer Chemother Pharmacol. 1999;43(3):233-40. [PubMed:9923554 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor
Specific Function:
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Inhibits Wnt signaling.
Gene Name:
RRM2
Uniprot ID:
P31350
Molecular Weight:
44877.25 Da
References
  1. Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. doi: 10.1517/13543780903173222. [PubMed:19715446 ]
  2. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. [PubMed:17852710 ]
  3. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
  4. Kline JP, Larson RA: Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review. Expert Opin Pharmacother. 2005 Dec;6(15):2711-8. [PubMed:16316309 ]
  5. Takahashi T, Kanazawa J, Akinaga S, Tamaoki T, Okabe M: Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration. Cancer Chemother Pharmacol. 1999;43(3):233-40. [PubMed:9923554 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor
Specific Function:
Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free radical center required for catalysis. Forms an active ribonucleotide reductase (RNR) complex with RRM1 which is expressed both in resting and proliferating cells in response to DNA damage.
Gene Name:
RRM2B
Uniprot ID:
Q7LG56
Molecular Weight:
40736.11 Da
References
  1. Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. doi: 10.1517/13543780903173222. [PubMed:19715446 ]
  2. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. [PubMed:17852710 ]
  3. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
  4. Kline JP, Larson RA: Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review. Expert Opin Pharmacother. 2005 Dec;6(15):2711-8. [PubMed:16316309 ]
  5. Takahashi T, Kanazawa J, Akinaga S, Tamaoki T, Okabe M: Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration. Cancer Chemother Pharmacol. 1999;43(3):233-40. [PubMed:9923554 ]
4. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
other/unknown
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
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:17139284 ]
  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:17016423 ]
  3. Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. doi: 10.1517/13543780903173222. [PubMed:19715446 ]
  4. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. [PubMed:17852710 ]
  5. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
  6. Kline JP, Larson RA: Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review. Expert Opin Pharmacother. 2005 Dec;6(15):2711-8. [PubMed:16316309 ]
  7. Hartman WR, Hentosh P: The antileukemia drug 2-chloro-2'-deoxyadenosine: an intrinsic transcriptional antagonist. Mol Pharmacol. 2004 Jan;65(1):227-34. [PubMed:14722255 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Protein kinase binding
Specific Function:
Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha com...
Gene Name:
POLA1
Uniprot ID:
P09884
Molecular Weight:
165911.405 Da
References
  1. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
  2. Kline JP, Larson RA: Clofarabine in the treatment of acute myeloid leukaemia and acute lymphoblastic leukaemia: a review. Expert Opin Pharmacother. 2005 Dec;6(15):2711-8. [PubMed:16316309 ]
  3. Takahashi T, Kanazawa J, Akinaga S, Tamaoki T, Okabe M: Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration. Cancer Chemother Pharmacol. 1999;43(3):233-40. [PubMed:9923554 ]
  4. Hartman WR, Hentosh P: The antileukemia drug 2-chloro-2'-deoxyadenosine: an intrinsic transcriptional antagonist. Mol Pharmacol. 2004 Jan;65(1):227-34. [PubMed:14722255 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Participates in DNA repair and in chromosomal DNA replication.
Gene Name:
POLE
Uniprot ID:
Q07864
Molecular Weight:
261515.525 Da
References
  1. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Dna-directed dna polymerase activity
Specific Function:
Participates in DNA repair and in chromosomal DNA replication.
Gene Name:
POLE2
Uniprot ID:
P56282
Molecular Weight:
59536.64 Da
References
  1. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Dna-directed dna polymerase activity
Specific Function:
Forms a complex with DNA polymerase epsilon subunit CHRAC1 and binds naked DNA, which is then incorporated into chromatin, aided by the nucleosome-remodeling activity of ISWI/SNF2H and ACF1.
Gene Name:
POLE3
Uniprot ID:
Q9NRF9
Molecular Weight:
16859.4 Da
References
  1. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Dna-directed dna polymerase activity
Specific Function:
May play a role in allowing polymerase epsilon to carry out its replication and/or repair function.
Gene Name:
POLE4
Uniprot ID:
Q9NR33
Molecular Weight:
12208.63 Da
References
  1. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inducer
General Function:
Purine-nucleoside phosphorylase activity
Specific Function:
The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate.
Gene Name:
PNP
Uniprot ID:
P00491
Molecular Weight:
32117.69 Da
References
  1. Bzowska A, Kazimierczuk Z: 2-Chloro-2'-deoxyadenosine (cladribine) and its analogues are good substrates and potent selective inhibitors of Escherichia coli purine-nucleoside phosphorylase. Eur J Biochem. 1995 Nov 1;233(3):886-90. [PubMed:8521855 ]
  2. Dumontet C, Fabianowska-Majewska K, Mantincic D, Callet Bauchu E, Tigaud I, Gandhi V, Lepoivre M, Peters GJ, Rolland MO, Wyczechowska D, Fang X, Gazzo S, Voorn DA, Vanier-Viornery A, MacKey J: Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562. Br J Haematol. 1999 Jul;106(1):78-85. [PubMed:10444166 ]
  3. Dumontet C, Bauchu EC, Fabianowska K, Lepoivre M, Wyczechowska D, Bodin F, Rolland MO: Common resistance mechanisms to nucleoside analogues in variants of the human erythroleukemic line K562. Adv Exp Med Biol. 1999;457:571-7. [PubMed:10500836 ]
  4. Takimoto T, Kubota M, Tsuruta S, Kitoh T, Tanizawa A, Akiyama Y, Kiriyama Y, Mikawa H: Changes in sensitivity to anticancer drugs during TPA-induced cellular differentiation in a human T-lymphoblastoid cell line (MOLT-4). Leukemia. 1988 Jul;2(7):443-6. [PubMed:3260648 ]
  5. Carson DA, Wasson DB, Lakow E, Kamatani N: Possible metabolic basis for the different immunodeficient states associated with genetic deficiencies of adenosine deaminase and purine nucleoside phosphorylase. Proc Natl Acad Sci U S A. 1982 Jun;79(12):3848-52. [PubMed:6808516 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Protein homodimerization activity
Specific Function:
Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.
Gene Name:
DCK
Uniprot ID:
P27707
Molecular Weight:
30518.315 Da
References
  1. Warnke C, Wiendl H, Hartung HP, Stuve O, Kieseier BC: Identification of targets and new developments in the treatment of multiple sclerosis--focus on cladribine. Drug Des Devel Ther. 2010 Jul 21;4:117-26. [PubMed:20689698 ]
  2. Sigal DS, Miller HJ, Schram ED, Saven A: Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood. 2010 Oct 21;116(16):2884-96. doi: 10.1182/blood-2010-02-246140. Epub 2010 Jul 15. [PubMed:20634380 ]
  3. Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. [PubMed:17852710 ]
  4. Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. doi: 10.1517/13543780903173222. [PubMed:19715446 ]
  5. Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. doi: 10.1016/j.bcp.2009.06.094. Epub 2009 Jul 1. [PubMed:19576186 ]
  6. Larson ML, Venugopal P: Clofarabine: a new treatment option for patients with acute myeloid leukemia. Expert Opin Pharmacother. 2009 Jun;10(8):1353-7. doi: 10.1517/14656560902997990. [PubMed:19463072 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Quaternary ammonium group transmembrane transporter activity
Specific Function:
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridiniu...
Gene Name:
SLC22A2
Uniprot ID:
O15244
Molecular Weight:
62579.99 Da
References
  1. Chen R, Nelson JA: Role of organic cation transporters in the renal secretion of nucleosides. Biochem Pharmacol. 2000 Jul 15;60(2):215-9. [PubMed:10825466 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Secondary active organic cation transmembrane transporter activity
Specific Function:
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine...
Gene Name:
SLC22A1
Uniprot ID:
O15245
Molecular Weight:
61153.345 Da
References
  1. Chen R, Nelson JA: Role of organic cation transporters in the renal secretion of nucleosides. Biochem Pharmacol. 2000 Jul 15;60(2):215-9. [PubMed:10825466 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Xenobiotic-transporting atpase activity
Specific Function:
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both from mitochondria to cytosol and from cytosol to extracellular space, and cellular export of hemin, and heme. Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from t...
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. de Wolf C, Jansen R, Yamaguchi H, de Haas M, van de Wetering K, Wijnholds J, Beijnen J, Borst P: Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides. Mol Cancer Ther. 2008 Sep;7(9):3092-102. doi: 10.1158/1535-7163.MCT-08-0427. Epub 2008 Sep 2. [PubMed:18765824 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Pyrimidine- and adenine-specific:sodium symporter activity
Specific Function:
Sodium-dependent, pyrimidine- and purine-selective. Involved in the homeostasis of endogenous nucleosides. Exhibits the transport characteristics of the nucleoside transport system cib or N3 subtype (N3/cib) (with marked transport of both thymidine and inosine). Employs a 2:1 sodium/nucleoside ratio. Also able to transport gemcitabine, 3'-azido-3'-deoxythymidine (AZT), ribavirin and 3-deazaurid...
Gene Name:
SLC28A3
Uniprot ID:
Q9HAS3
Molecular Weight:
76929.61 Da
References
  1. Badagnani I, Chan W, Castro RA, Brett CM, Huang CC, Stryke D, Kawamoto M, Johns SJ, Ferrin TE, Carlson EJ, Burchard EG, Giacomini KM: Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3). Pharmacogenomics J. 2005;5(3):157-65. [PubMed:15738947 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23