Tmic
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Record Information
Version2.0
Creation Date2009-07-21 20:28:38 UTC
Update Date2014-12-24 20:25:55 UTC
Accession NumberT3D3020
Identification
Common NameMitoxantrone
ClassSmall Molecule
DescriptionMitoxantrone is only found in individuals that have used or taken this drug. It is an anthracenedione-derived antineoplastic agent. Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
Compound Type
  • Amide
  • Amine
  • Analgesic
  • Antineoplastic Agent
  • Drug
  • Ester
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
1,4-DIHYDROXY-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)-9,10-anthracenedione
Mitoxanthrone
Mitoxantron
Mitoxantrona
Mitoxantronum
Novantrone
Chemical FormulaC22H28N4O6
Average Molecular Mass444.481 g/mol
Monoisotopic Mass444.201 g/mol
CAS Registry Number65271-80-9
IUPAC Name1,4-dihydroxy-5,8-bis({2-[(2-hydroxyethyl)amino]ethyl}amino)-9,10-dihydroanthracene-9,10-dione
Traditional Namemitoxantrone
SMILESOCCNCCNC1=C2C(=O)C3=C(O)C=CC(O)=C3C(=O)C2=C(NCCNCCO)C=C1
InChI IdentifierInChI=1S/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2
InChI KeyInChIKey=KKZJGLLVHKMTCM-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as anthraquinones. These are organic compounds containing either anthracene-9,10-quinone, 1,4-anthraquinone, or 1,2-anthraquinone.
KingdomOrganic compounds
Super ClassBenzenoids
ClassAnthracenes
Sub ClassAnthraquinones
Direct ParentAnthraquinones
Alternative Parents
Substituents
  • 9,10-anthraquinone
  • Anthraquinone
  • Aryl ketone
  • 1-hydroxy-2-unsubstituted benzenoid
  • Secondary aliphatic/aromatic amine
  • Vinylogous acid
  • Vinylogous amide
  • 1,2-aminoalcohol
  • Ketone
  • Secondary amine
  • Secondary aliphatic amine
  • Alkanolamine
  • Organic oxide
  • Organopnictogen compound
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Amine
  • Alcohol
  • Hydrocarbon derivative
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateLiquid
AppearanceNot Available
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility7.34e-01 g/L
LogP-3.1
Predicted Properties
PropertyValueSource
Water Solubility0.73 g/LALOGPS
logP0.91ALOGPS
logP1.19ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)9.78ChemAxon
pKa (Strongest Basic)9.08ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area163.18 ŲChemAxon
Rotatable Bond Count12ChemAxon
Refractivity123.53 m³·mol⁻¹ChemAxon
Polarizability48.49 ųChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-03k9-4008900000-031c3e5b5c6fbec57bdcView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-052b-3100094000-753b733851babd16586eView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-0a4j-0394000000-5f26812f41567533fe71View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0002-0012900000-147e3b4eed2bd9c29e51View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0a4j-0394000000-5f26812f41567533fe71View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0002-3003900000-9c369ecea59cd969c230View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-000i-9004200000-d4db7c5244eae35ee957View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000m-9023000000-a3182f5d9afc8da8c7bcView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-1001900000-a08d98fc5346d9d02409View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-002f-4015900000-de9bc44a9432611d1ba2View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-03dl-9214200000-bbad802d490cbc39d94dView in MoNA
Toxicity Profile
Route of ExposureIntravenous injection. Poorly absorbed following oral administration.
Mechanism of ToxicityMitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
MetabolismHepatic Half Life: 75 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)2B, possibly carcinogenic to humans. (3)
Uses/SourcesFor the treatment of secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis. Mitoxantrone is an Anthracenedione (not an anthracycline) antineoplastic agent.
Minimum Risk LevelNot Available
Health EffectsCardiomyopathy is a particularly concerning effect as it is irreversible. [Wikipedia]
SymptomsSevere leukopenia with infection.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01204
HMDB IDHMDB15335
PubChem Compound ID4212
ChEMBL IDCHEMBL58
ChemSpider ID4067
KEGG IDC11195
UniProt IDNot Available
OMIM ID
ChEBI ID50729
BioCyc IDNot Available
CTD IDNot Available
Stitch IDMitoxantrone
PDB IDMIX
ACToR IDNot Available
Wikipedia LinkMitoxantrone
References
Synthesis Reference

DrugSyn.org

MSDSLink
General References
  1. Fox EJ: Management of worsening multiple sclerosis with mitoxantrone: a review. Clin Ther. 2006 Apr;28(4):461-74. [16750460 ]
  2. Drugs.com [Link]
  3. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Ubiquitin binding
Specific Function:
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes. May play a role in regulating the period length of ARNTL/BMAL1 transcriptional oscillation (By similarity).
Gene Name:
TOP2A
Uniprot ID:
P11388
Molecular Weight:
174383.88 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC505.3 uMNot AvailableBindingDB 50003674
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Takeda K, Shinohara K, Kameda N, Ariyoshi K: A case of therapy-related acute myeloblastic leukemia with t(16;21)(q24;q22) after chemotherapy with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and the alkylating agent, cyclophosphamide. Int J Hematol. 1998 Feb;67(2):179-86. [9631585 ]
  3. McPherson JP, Deffie AM, Jones NR, Brown GA, Deuchars KL, Goldenberg GJ: Selective sensitization of adriamycin-resistant P388 murine leukemia cells to antineoplastic agents following transfection with human DNA topoisomerase II alpha. Anticancer Res. 1997 Nov-Dec;17(6D):4243-52. [9494516 ]
  4. Wang H, Mao Y, Zhou N, Hu T, Hsieh TS, Liu LF: Atp-bound topoisomerase ii as a target for antitumor drugs. J Biol Chem. 2001 May 11;276(19):15990-5. Epub 2001 Feb 23. [11278845 ]
  5. Satherley K, de Souza L, Neale MH, Alexander RA, Myatt N, Foss AJ, Hungerford JL, Hickson ID, Cree IA: Relationship between expression of topoisomerase II isoforms and chemosensitivity in choroidal melanoma. J Pathol. 2000 Oct;192(2):174-81. [11004693 ]
  6. Mao Y, Yu C, Hsieh TS, Nitiss JL, Liu AA, Wang H, Liu LF: Mutations of human topoisomerase II alpha affecting multidrug resistance and sensitivity. Biochemistry. 1999 Aug 17;38(33):10793-800. [10451375 ]
  7. Hasinoff BB, Liang H, Wu X, Guziec LJ, Guziec FS Jr, Marshall K, Yalowich JC: The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds. Bioorg Med Chem. 2008 Apr 1;16(7):3959-68. doi: 10.1016/j.bmc.2008.01.033. Epub 2008 Jan 26. [18258442 ]
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 the brain. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. Implicated in the efflux of numerous drugs and xenobiotics: mitoxantrone, the photosensitizer pheophorbide, camptothecin, methotrexate, azidothymidine (AZT), and the anthracyclines daunorubicin and doxorubicin.
Gene Name:
ABCG2
Uniprot ID:
Q9UNQ0
Molecular Weight:
72313.47 Da
References
  1. Ross DD, Yang W, Abruzzo LV, Dalton WS, Schneider E, Lage H, Dietel M, Greenberger L, Cole SP, Doyle LA: Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J Natl Cancer Inst. 1999 Mar 3;91(5):429-33. [10070941 ]
  2. Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, Floot BG, Schellens JH: Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 1999 Sep 15;59(18):4559-63. [10493507 ]
  3. Brangi M, Litman T, Ciotti M, Nishiyama K, Kohlhagen G, Takimoto C, Robey R, Pommier Y, Fojo T, Bates SE: Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res. 1999 Dec 1;59(23):5938-46. [10606239 ]
  4. Rocchi E, Khodjakov A, Volk EL, Yang CH, Litman T, Bates SE, Schneider E: The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem Biophys Res Commun. 2000 Apr 29;271(1):42-6. [10777678 ]
  5. Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, Schinkel AH: Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000 Oct 18;92(20):1651-6. [11036110 ]
3. 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. Mazerski J, Martelli S, Borowski E: The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations. Acta Biochim Pol. 1998;45(1):1-11. [9701490 ]
  2. Hajihassan Z, Rabbani-Chadegani A: Studies on the binding affinity of anticancer drug mitoxantrone to chromatin, DNA and histone proteins. J Biomed Sci. 2009 Mar 11;16:31. doi: 10.1186/1423-0127-16-31. [19284573 ]
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5076.3 uMNot AvailableBindingDB 50003674
References
  1. Kemp CA, Flanagan JU, van Eldik AJ, Marechal JD, Wolf CR, Roberts GC, Paine MJ, Sutcliffe MJ: Validation of model of cytochrome P450 2D6: an in silico tool for predicting metabolism and inhibition. J Med Chem. 2004 Oct 21;47(22):5340-6. [15481972 ]
General Function:
Monovalent cation:proton antiporter activity
Specific Function:
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, ganciclovir and also the zwitterionic cephalosporin, cephalexin and cephradin. Seems to also play a role in the uptake of oxaliplatin (a new platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes.
Gene Name:
SLC47A1
Uniprot ID:
Q96FL8
Molecular Weight:
61921.585 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.19 uMNot AvailableBindingDB 50003674
IC500.4 uMNot AvailableBindingDB 50003674
IC500.53 uMNot AvailableBindingDB 50003674
References
  1. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]
General Function:
Drug transmembrane transporter activity
Specific Function:
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, and ganciclovir. Responsible for the secretion of cationic drugs across the brush border membranes.
Gene Name:
SLC47A2
Uniprot ID:
Q86VL8
Molecular Weight:
65083.915 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.83 uMNot AvailableBindingDB 50003674
References
  1. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]
General Function:
Transporter activity
Specific Function:
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.
Gene Name:
ABCC1
Uniprot ID:
P33527
Molecular Weight:
171589.5 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.0015 uMNot AvailableBindingDB 50003674
IC500.0019 uMNot AvailableBindingDB 50003674
References
  1. Morrow CS, Peklak-Scott C, Bishwokarma B, Kute TE, Smitherman PK, Townsend AJ: Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Mol Pharmacol. 2006 Apr;69(4):1499-505. Epub 2006 Jan 24. [16434618 ]
General Function:
Guanyl-nucleotide exchange factor activity
Specific Function:
Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Required for normal platelet aggregation and blood coagulation.
Gene Name:
P2RY12
Uniprot ID:
Q9H244
Molecular Weight:
39438.355 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 50003674
References
  1. Baqi Y, Atzler K, Kose M, Glanzel M, Muller CE: High-affinity, non-nucleotide-derived competitive antagonists of platelet P2Y12 receptors. J Med Chem. 2009 Jun 25;52(12):3784-93. doi: 10.1021/jm9003297. [19463000 ]
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, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin-dependent kinase II and LCK tyrosine kinase.
Gene Name:
SLC22A1
Uniprot ID:
O15245
Molecular Weight:
61153.345 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5043.9 uMNot AvailableBindingDB 50003674
References
  1. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]
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-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity.
Gene Name:
SLC22A2
Uniprot ID:
O15244
Molecular Weight:
62579.99 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5073.3 uMNot AvailableBindingDB 50003674
References
  1. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]
General Function:
Toxin transporter activity
Specific Function:
Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.
Gene Name:
SLC22A3
Uniprot ID:
O75751
Molecular Weight:
61279.485 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5060.5 uMNot AvailableBindingDB 50003674
References
  1. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22. [23241029 ]
General Function:
Protein tyrosine kinase activity
Specific Function:
Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.
Gene Name:
BTK
Uniprot ID:
Q06187
Molecular Weight:
76280.71 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC501 uMNot AvailableBindingDB 50003674
References
  1. Wan X, Zhang W, Li L, Xie Y, Li W, Huang N: A new target for an old drug: identifying mitoxantrone as a nanomolar inhibitor of PIM1 kinase via kinome-wide selectivity modeling. J Med Chem. 2013 Mar 28;56(6):2619-29. doi: 10.1021/jm400045y. Epub 2013 Mar 15. [23442188 ]