DT-Web

DB01280 - Nelarabine


Identification
Name Nelarabine
Accession Number DB01280
Type small molecule
Description Nelarabine is a chemotherapy drug used in T-cell acute lymphoblastic leukemia. Nelarabine is a purine nucleoside analog converted to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), resulting in inhibition of DNA synthesis and cytotoxicity.
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 297.2673
Groups approved
Monoisotopic Weight 297.107318615
Pharmacology
Indication For the treatment of pediatric and adult patients with acute T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.
Mechanism of action Once nelarabine is metabolized into ara-GTP, the metabolite accumulates in leukemic blasts and incorporates into DNA to exert its S phase-specific cytotoxic effects, leading to the induction of fragmentation and apoptosis. Ara-GTP competes with endogenous deoxyGTP (dGTP) for incorporation into DNA. Once ara-GTP is incorporated at the 3' end of DNA, further DNA elongation is inhibited, which signals apoptosis and leads to cellular destruction. Additional cytotoxic activities may exist, but these are not fully understood.
Absorption Not Available
Protein binding Nelarabine and ara-G are not substantially bound to human plasma proteins (<25%) in vitro, and binding is independent of nelarabine or ara-G concentrations up to 600 mM.
Biotransformation The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolyzed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid. Ring opening of uric acid followed by further oxidation results in the formation of allantoin.
Route of elimination Excretion: Nelarabine and ara-G are partially eliminated by the kidneys.
Toxicity A single IV dose of 4,800 mg/m^2 was lethal in monkeys, and was associated with CNS signs including reduced/shallow respiration, reduced reflexes, and flaccid muscle tone. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions Not Available

Targets


DNA
Name DNA
Gene Name Not Available
Pharmacological action yes
Actions incorporation into and destabilization
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
  • Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. - Pubmed
  • DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. - Pubmed
  • Sanford M, Lyseng-Williamson KA: Nelarabine. Drugs. 2008;68(4):439-47. - Pubmed
  • Reilly KM, Kisor DF: Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. Onco Targets Ther. 2009 Feb 18;2:219-28. - Pubmed
  • Cooper TM: Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manag. 2007 Dec;3(6):1135-41. - Pubmed
  • Curbo S, Karlsson A: Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92. - Pubmed
  • Gandhi V, Keating MJ, Bate G, Kirkpatrick P: Nelarabine. Nat Rev Drug Discov. 2006 Jan;5(1):17-8. - Pubmed
DTHybrid score Not Available
DNA polymerase alpha catalytic subunit
Name DNA polymerase alpha catalytic subunit
Gene Name POLA1
Pharmacological action unknown
Actions inhibitor
References
  • Ono K, Ohashi A, Yamamoto A, Matsukage A, Takahasi T, Saneyoshi M, Ueda T: Inhibitory effects of 9-beta-D-arabinofuranosylguanine 5'-triphosphate and 9-beta-D-arabinofuranosyladenine 5'-triphosphate on DNA polymerases from murine cells and oncornavirus. Cancer Res. 1979 Nov;39(11):4673-80. - Pubmed
  • Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. - Pubmed
  • Curbo S, Karlsson A: Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92. - Pubmed
  • Rodriguez CO Jr, Stellrecht CM, Gandhi V: Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. Blood. 2003 Sep 1;102(5):1842-8. Epub 2003 May 15. - Pubmed
DTHybrid score 0.7855

Enzymes


Adenosine deaminase
Name Adenosine deaminase
Gene Name ADA
Actions substrate
References
  • Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. - Pubmed
  • DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. - Pubmed
  • Reilly KM, Kisor DF: Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. Onco Targets Ther. 2009 Feb 18;2:219-28. - Pubmed
  • Cooper TM: Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manag. 2007 Dec;3(6):1135-41. - Pubmed
  • Cohen MH, Johnson JR, Justice R, Pazdur R: FDA drug approval summary: nelarabine (Arranon) for the treatment of T-cell lymphoblastic leukemia/lymphoma. Oncologist. 2008 Jun;13(6):709-14. - Pubmed
  • Gandhi V, Keating MJ, Bate G, Kirkpatrick P: Nelarabine. Nat Rev Drug Discov. 2006 Jan;5(1):17-8. - Pubmed
DTHybrid score 1.5686
Deoxycytidine kinase
Name Deoxycytidine kinase
Gene Name DCK
Actions substrate
References
  • Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. - Pubmed
  • DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. - Pubmed
  • Reilly KM, Kisor DF: Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. Onco Targets Ther. 2009 Feb 18;2:219-28. - Pubmed
  • Cooper TM: Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manag. 2007 Dec;3(6):1135-41. - Pubmed
  • DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, Gockerman JP, Mitchell BS, Appelbaum FR, Larson RA: Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood. 2007 Jun 15;109(12):5136-42. Epub 2007 Mar 7. - Pubmed
DTHybrid score 0.8919
Deoxyguanosine kinase, mitochondrial
Name Deoxyguanosine kinase, mitochondrial
Gene Name DGUOK
Actions substrate
References
  • Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. - Pubmed
  • DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. - Pubmed
  • Reilly KM, Kisor DF: Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. Onco Targets Ther. 2009 Feb 18;2:219-28. - Pubmed
  • Cooper TM: Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manag. 2007 Dec;3(6):1135-41. - Pubmed
  • DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, Gockerman JP, Mitchell BS, Appelbaum FR, Larson RA: Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood. 2007 Jun 15;109(12):5136-42. Epub 2007 Mar 7. - Pubmed
DTHybrid score 0.7022

Predictions


Id Partner name Gene Name Score
360 Ribonucleoside-diphosphate reductase large subunit RRM1 0.2571
6171 Solute carrier family 28 member 3 SLC28A3 0.1423
2222 Equilibrative nucleoside transporter 1 SLC29A1 0.1248
3690 Class B acid phosphatase precursor aphA 0.0952
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.07
1064 DNA (cytosine-5)-methyltransferase 1 DNMT1 0.0636
6112 DNA polymerase epsilon subunit 3 POLE3 0.0512
6111 DNA polymerase epsilon subunit 4 POLE4 0.0512
6108 Ribonucleoside-diphosphate reductase subunit M2 B RRM2B 0.0511
6110 DNA polymerase epsilon subunit 2 POLE2 0.0511
6109 DNA polymerase epsilon catalytic subunit A POLE 0.0511
338 DNA polymerase UL30 0.0376
379 DNA polymerase UL54 0.0376
697 DNA polymerase ORF28 0.0376
2482 DNA polymerase 43 0.0376
4104 DNA polymerase BALF5 0.0376
4218 Ribonucleoside-diphosphate reductase M2 subunit RRM2 0.037
3611 Cytidine deaminase cdd 0.0288
3707 Cytidine deaminase cdd 0.0288
4211 Cytidine deaminase CDA 0.0288
509 Thymidine kinase TK 0.0282
570 Thymidine kinase TK 0.0282
2559 Thymidine kinase TK 0.0282
3430 Thymidine kinase tdk 0.0282
3518 Thymidine kinase TK 0.0282
5301 Thymidine kinase tdk 0.0282
5771 Thymidine kinase ORF36 0.0282
7009 Thymidine kinase ORF36 0.0282
6144 Solute carrier family 22 member 2 SLC22A2 0.0273
6145 Solute carrier family 22 member 1 SLC22A1 0.0263
24 Thymidylate synthase TMP1 0.0246
359 Thymidylate synthase TYMS 0.0246
2626 Thymidylate synthase thyA 0.0246
2729 Thymidylate synthase thyA 0.0246
5352 Thymidylate synthase THYA 0.0246
277 Purine nucleoside phosphorylase PNP 0.0231
2870 Purine nucleoside phosphorylase punA 0.0231
2945 Purine nucleoside phosphorylase punA 0.0231
4659 Purine nucleoside phosphorylase TM_1596 0.0231
4825 Purine nucleoside phosphorylase TTHA1435 0.0231
702 UMP-CMP kinase CMPK1 0.0222
1043 Trifunctional purine biosynthetic protein adenosine-3 [Includes: Phosphoribosylamine--glycine ligase GART 0.0205
6044 Serum paraoxonase/lactonase 3 PON3 0.0199
6148 Multidrug resistance-associated protein 7 ABCC10 0.0194
2287 Bifunctional purine biosynthesis protein PURH [Includes: Phosphoribosylaminoimidazolecarboxamide formyltransferase ATIC 0.0176
268 Adenosine A2b receptor ADORA2B 0.0175
1830 5'-nucleotidase NT5E 0.0163
125 DNA polymerase beta POLB 0.0153
204 cGMP-specific 3',5'-cyclic phosphodiesterase PDE5A 0.0137
1178 Adenosine A2a receptor ADORA2A 0.0137
16 Adenosine A1 receptor ADORA1 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
390 Adenosine A3 receptor ADORA3 0.013
1971 cAMP-specific 3',5'-cyclic phosphodiesterase 4A PDE4A 0.0128
1588 Multidrug resistance protein 1 ABCB1 0.0127
3811 Cytochrome P450 19A1 CYP19A1 0.0119
6021 Adenosine kinase ADK 0.0117
695 cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A PDE10A 0.0113
2164 Multidrug resistance-associated protein 4 ABCC4 0.0112
4512 Cytochrome P450 3A4 CYP3A4 0.0103
4200 Cytochrome P450 1A2 CYP1A2 0.0101
342 P protein [Includes: DNA-directed DNA polymerase P 0.0099
612 P protein [Includes: DNA-directed DNA polymerase P 0.0099
6143 Solute carrier family 22 member 7 SLC22A7 0.0098
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
6136 Multidrug resistance-associated protein 5 ABCC5 0.0081
5626 Nucleoside diphosphate kinase B NME2 0.0079
5294 Nucleoside diphosphate kinase A NME1 0.007
4757 Cytochrome P450 2C9 CYP2C9 0.0065
4119 Cytochrome P450 2D6 CYP2D6 0.0063
6107 Cytochrome P450 3A7 CYP3A7 0.0055
4118 Cytochrome P450 3A5 CYP3A5 0.0052
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0046
6147 Solute carrier family 22 member 3 SLC22A3 0.0046
4122 Histone deacetylase 2 HDAC2 0.0042
862 Multidrug resistance-associated protein 1 ABCC1 0.004
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0038
485 cGMP-inhibited 3',5'-cyclic phosphodiesterase A PDE3A 0.0036
541 cAMP-specific 3',5'-cyclic phosphodiesterase 4B PDE4B 0.0033
1898 Cytochrome P450 1B1 CYP1B1 0.0027
6024 Cytochrome P450 1A1 CYP1A1 0.0022
6013 Cytochrome P450 2E1 CYP2E1 0.0021
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
4924 Cytochrome P450 2C8 CYP2C8 0.0019
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
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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