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Record Information
Version2.0
Creation Date2014-09-11 05:16:01 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4774
Identification
Common NameCladribine
ClassSmall Molecule
DescriptionAn antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia.
Compound Type
  • Amine
  • Antineoplastic Agent
  • Drug
  • Ether
  • Immunosuppressive Agent
  • Metabolite
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(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
Chlorodeoxyadenosine
Cladribina
Cladribinum
CldAdo
Leustatin
Litak
Movectro
Mylinax
Chemical FormulaC10H12ClN5O3
Average Molecular Mass285.687 g/mol
Monoisotopic Mass285.063 g/mol
CAS Registry Number4291-63-8
IUPAC Name(2R,3S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol
Traditional Namecladribine
SMILES[H][C@]1(O)C[C@@]([H])(O[C@]1([H])CO)N1C=NC2=C(N)N=C(Cl)N=C12
InChI IdentifierInChI=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
InChI KeyInChIKey=PTOAARAWEBMLNO-KVQBGUIXSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as purine 2'-deoxyribonucleosides. Purine 2'-deoxyribonucleosides are compounds consisting of a purine linked to a ribose which lacks a hydroxyl group at position 2.
KingdomOrganic compounds
Super ClassNucleosides, nucleotides, and analogues
ClassPurine nucleosides
Sub ClassPurine 2'-deoxyribonucleosides
Direct ParentPurine 2'-deoxyribonucleosides
Alternative Parents
Substituents
  • Purine 2'-deoxyribonucleoside
  • 6-aminopurine
  • Imidazopyrimidine
  • Purine
  • Aminopyrimidine
  • 2-halopyrimidine
  • Halopyrimidine
  • N-substituted imidazole
  • Aryl chloride
  • Aryl halide
  • Pyrimidine
  • Imidolactam
  • Tetrahydrofuran
  • Heteroaromatic compound
  • Imidazole
  • Azole
  • Secondary alcohol
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Organohalogen compound
  • Primary alcohol
  • Primary amine
  • Amine
  • Alcohol
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Organic oxygen compound
  • Organochloride
  • Organonitrogen compound
  • Organooxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point215°C
Boiling PointNot Available
Solubility6.35e+00 g/L
LogP-0.1
Predicted Properties
PropertyValueSource
Water Solubility6.35 g/LALOGPS
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 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity67.18 m³·mol⁻¹ChemAxon
Polarizability25.93 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0006-9140000000-2241274903b14d6388f8JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-006x-9003100000-a89891be7a06bbd5506cJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-00di-1910000000-ab013e8ee7a199f7832aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-00e9-2900000000-e03a0a91db8b01dbf975JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-00di-1910000000-ab013e8ee7a199f7832aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-00e9-2900000000-e03a0a91db8b01dbf975JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 15V, Negativesplash10-001i-0190000000-05b17eee8a4c08986cb6JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 30V, Negativesplash10-001j-0960000000-0d9006c856af92145663JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 90V, Negativesplash10-0159-9800000000-8fab0ce14314864acddbJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 75V, Negativesplash10-001i-3900000000-1e50884799359687c7e6JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 45V, Negativesplash10-001i-0900000000-212e968f1960bfdb6eb9JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 60V, Negativesplash10-001i-1900000000-02d458221e661841d56fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 35V, Negativesplash10-001i-0790000000-67b2d564dceedaaa13f9JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 90V, Positivesplash10-001i-1900000000-a7de88853c9f6d670469JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 60V, Positivesplash10-00di-2900000000-cdfa1c97765dc0e2b44dJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 75V, Positivesplash10-0089-1900000000-e6ecaf5468250a1f5477JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 15V, Positivesplash10-00di-0930000000-7147248d1818af3d9fe1JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-00di-0900000000-6e9123e18d8f115cbf6fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 30V, Positivesplash10-00di-0900000000-27a9b8fbe0ffb19d00b6JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 45V, Positivesplash10-00di-2900000000-ab1e61284e7768836426JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0920000000-8e9ebddc65823aa84924JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00di-0900000000-0b29ceb8b9b509f8d741JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00di-0900000000-f0f21af02a8d1d299e4aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00e9-0290000000-7a1cc2a1753c44b0a43dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-014i-0910000000-7d61665b0d4c6756760fJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00lr-1900000000-345fc7c0125888e844c5JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0900000000-fa3ec9f7b8f59958cd43JSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureOral bioavailability is 34 to 48%.
Mechanism of ToxicityCladribine 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-2ду_-deoxyadenosine 5ду_-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.
MetabolismMetabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate Half Life: 5.4 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor 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.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSymptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00242
HMDB IDHMDB14387
PubChem Compound ID20279
ChEMBL IDCHEMBL1619
ChemSpider ID19105
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID567361
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDCL9
ACToR IDNot Available
Wikipedia LinkCladribine
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.

MSDSLink
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. [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. [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. [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. [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. [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. [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. [19463072 ]
  8. Dimopoulos MA, Weber DM, Kantarjian H, Keating M, Alexanian R: 2Chlorodeoxyadenosine therapy of patients with Waldenstrom macroglobulinemia previously treated with fludarabine. Ann Oncol. 1994 Mar;5(3):288-9. [7514439 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

1. DNA
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. [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. [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. [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. [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. [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. [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. [14722255 ]
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. [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. [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. [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. [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. [6808516 ]
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. [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. [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. [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. [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. [9923554 ]
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. [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. [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. [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. [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. [9923554 ]
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. [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. [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. [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. [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. [9923554 ]
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 complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes.
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. [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. [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. [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. [14722255 ]
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. [19576186 ]
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. [19576186 ]
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. [19576186 ]
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. [19576186 ]
General Function:
Zinc ion binding
Specific Function:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:
AR
Uniprot ID:
P10275
Molecular Weight:
98987.9 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.000589 uMTox21_AR_LUC_MDAKB2_AgonistTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Not Available
Specific Function:
Not Available
Gene Name:
TP53
Uniprot ID:
P04637
Molecular Weight:
43652.79 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.388 uMAPR_p53Act_24h_upApredica
AC500.388 uMAPR_p53Act_72h_upApredica
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC504.39 uMATG_ERE_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Metal ion binding
Specific Function:
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name:
PDE4A
Uniprot ID:
P27815
Molecular Weight:
98142.155 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC507.38 uMNVS_ENZ_hPDE4A1Novascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]