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Identification
NameNilotinib
Accession NumberDB04868
Typesmall molecule
Groupsapproved, investigational
Description

Nilotinib, also known as AMN107, is a tyrosine kinase inhibitor under investigation as a possible treatment for chronic myelogenous leukemia (CML). In June 2006, a Phase I clinical trial found nilotinib has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib (Gleevec®), another tyrosine kinase inhibitor currently used as a first-line treatment. [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
AMN 107Not AvailableNot Available
AMN-107Not AvailableNot Available
AMN107Not AvailableNot Available
NilotinibumNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
TasignaNovartis
Brand mixturesNot Available
Categories
CAS number641571-10-0
WeightAverage: 529.5158
Monoisotopic: 529.183792976
Chemical FormulaC28H22F3N7O
InChI KeyHHZIURLSWUIHRB-UHFFFAOYSA-N
InChI
InChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37)
IUPAC Name
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide
SMILES
CC1=CN(C=N1)C1=CC(=CC(NC(=O)C2=CC(NC3=NC=CC(=N3)C3=CN=CC=C3)=C(C)C=C2)=C1)C(F)(F)F
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBenzamides
Direct parentN-phenylbenzamides
Alternative parentsPyridinylpyrimidines; Phenylimidazoles; Anilides; Aminobenzamides; Benzoyl Derivatives; Toluenes; N-substituted Imidazoles; Pyridines and Derivatives; Secondary Carboxylic Acid Amides; Enolates; Carboxylic Acids; Polyamines; Secondary Amines; Organofluorides; Alkyl Fluorides
Substituentspyridinylpyrimidine; 1-phenylimidazole; acetanilide; aminobenzamide; benzoyl; toluene; n-substituted imidazole; pyrimidine; pyridine; azole; imidazole; carboxamide group; secondary carboxylic acid amide; secondary amine; enolate; carboxylic acid derivative; polyamine; carboxylic acid; organonitrogen compound; organofluoride; organohalogen; amine; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the n-phenylbenzamides.
Pharmacology
IndicationFor the potential treatment of various leukemias, including chronic myeloid leukemia (CML).
PharmacodynamicsNilotinib is a transduction inhibitor that targets BCR-ABL, c-kit and PDGF, for the potential treatment of various leukemias, including chronic myeloid leukemia (CML).
Mechanism of actionChronic myelogenous leukaemia (CML) is caused by the BCR-ABL oncogene. Nilotinib inhibits the tyrosine kinase activity of the BCR-ABL protein. Nilotinib fits into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib, over-riding resistance caused by mutations. The ability of AMN107 to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukaemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests potential use of AMN107 for myeloproliferative diseases characterised by these kinase fusions (Stover et al, 2005; Weisberg et al, 2005). AMN107 also inhibits the c-Kit receptor kinase, including the D816V-mutated variant of KIT, at pharmacologically achievable concentrations, supporting potential utility in the treatment of mastocytosis, and gastrointestinal stromal tumours (Weisberg et al, 2005; von Bubnoff et al, 2005; Gleixner et al, 2006).
AbsorptionOrally available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half life15 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9066
Caco-2 permeable - 0.5792
P-glycoprotein substrate Non-substrate 0.6879
P-glycoprotein inhibitor I Inhibitor 0.556
P-glycoprotein inhibitor II Inhibitor 0.6002
Renal organic cation transporter Non-inhibitor 0.8253
CYP450 2C9 substrate Non-substrate 0.8178
CYP450 2D6 substrate Non-substrate 0.8547
CYP450 3A4 substrate Substrate 0.5552
CYP450 1A2 substrate Inhibitor 0.7324
CYP450 2C9 substrate Non-inhibitor 0.5739
CYP450 2D6 substrate Non-inhibitor 0.8275
CYP450 2C19 substrate Inhibitor 0.5554
CYP450 3A4 substrate Inhibitor 0.6784
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7862
Ames test Non AMES toxic 0.5204
Carcinogenicity Non-carcinogens 0.8175
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.6343 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9961
hERG inhibition (predictor II) Inhibitor 0.8458
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
PackagersNot Available
Dosage formsNot Available
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States71697912003-07-042023-07-04
Canada24916322009-11-102023-07-04
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility2.01e-03 g/lALOGPS
logP4.51ALOGPS
logP4.41ChemAxon
logS-5.4ALOGPS
pKa (strongest acidic)11.86ChemAxon
pKa (strongest basic)6.3ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count6ChemAxon
hydrogen donor count2ChemAxon
polar surface area97.62ChemAxon
rotatable bond count7ChemAxon
refractivity152.85ChemAxon
polarizability52.35ChemAxon
number of rings5ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Yanling WANG, Jie LI, Vinod Kumar KANSAL, Jirang ZHU, Revital LIFSHITZ-LIRON, Dhirenkumar N. MISTRY, Sanjay L. VASOYA, Sundaraselvan ARIYAMUTHU, Gideon PILARSKI, Xungui HE, “NILOTINIB INTERMEDIATES AND PREPARATION THEREOF.” U.S. Patent US20100016590, issued January 21, 2010.

US20100016590
General Reference
  1. Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG: Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. Pubmed
  2. Maekawa T, Ashihara E, Kimura S: The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias. Int J Clin Oncol. 2007 Oct;12(5):327-40. Epub 2007 Oct 22. Pubmed
  3. Breccia M, Cannella L, Nanni M, Stefanizzi C, Alimena G: Nilotinib Can Override Dasatinib Resistance in Chronic Myeloid Leukemia Patients with Secondary Resistance to Imatinib First-Line Therapy. Acta Haematol. 2007 Sep 20;118(3):162-164. Pubmed
  4. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O’brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P: Nilotinib (formerly AMN107), a highly selective Bcr-Abl tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Aug 22;. Pubmed
  5. Jabbour E, Cortes J, Giles F, O’Brien S, Kantarijan H: Drug evaluation: Nilotinib – a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond. IDrugs. 2007 Jul;10(7):468-79. Pubmed
External Links
ResourceLink
PubChem Compound644241
PubChem Substance99443226
ChemSpider559260
ChEBI52172
ChEMBLCHEMBL255863
PharmGKBPA165958345
WikipediaNilotinib
ATC CodesL01XE08
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(68.9 KB)
Interactions
Drug Interactions
Drug
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
BendamustineP-glycoprotein (MDR-1) efflux transporter increases bendamustine levels.
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Nilotinib prescribing information recommends avoiding concurrent use of nilotinib with strong inhibitors of CYP3A4.
EtravirineNilotinib, when used concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
TacrolimusMay cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
TamoxifenNilotinib may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.
TamsulosinNilotinib, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Nilotinib is initiated, discontinued, or dose changed.
TelithromycinTelithromycin may reduce clearance of Nilotinib. Concomitant therapy should be avoided.
ThiothixeneMay cause additive QTc-prolonging effects. Concomitant therapy should be avoided.
TopotecanThe p-glycoprotein inhibitor, Nilotinib, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
ToremifeneMay cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
TramadolNilotinib may decrease the effect of Tramadol by decreasing active metabolite production.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
TretinoinThe moderate CYP2C8 inhibitor, Nilotinib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Nilotinib is initiated, discontinued to dose changed.
TrimipramineMay cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
VoriconazoleVoriconazole may increase the serum concentration of nilotinib by inhibiting its metabolism by CYP3A4. Additive QTc prolongation may also occur. Concomitant therapy should be avoided.
VorinostatAdditive QTc prolongation may occur. Concomitant therapy should be avoided.
ZiprasidoneAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
ZuclopenthixolAdditive QTc-prolonging effects increases risk of cardiac arrhythmias. Concomitant therapy should be avoided.
Zuclopenthixol acetateAdditive QTc-prolonging effects increases risk of cardiac arrhythmias. Concomitant therapy should be avoided.
Zuclopenthixol decanoateAdditive QTc-prolonging effects increases risk of cardiac arrhythmias. Concomitant therapy should be avoided.
Food InteractionsNot Available

Targets

1. Tyrosine-protein kinase ABL1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Tyrosine-protein kinase ABL1 P00519 Details

References:

  1. Maekawa T, Ashihara E, Kimura S: The Bcr-Abl tyrosine kinase inhibitor imatinib and promising new agents against Philadelphia chromosome-positive leukemias. Int J Clin Oncol. 2007 Oct;12(5):327-40. Epub 2007 Oct 22. Pubmed
  2. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O’brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P: Nilotinib (formerly AMN107), a highly selective Bcr-Abl tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Aug 22;. Pubmed
  3. Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD: AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006 Jun 19;94(12):1765-9. Epub 2006 May 23. Pubmed
  4. Swords R, Mahalingam D, Padmanabhan S, Carew J, Giles F: Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib. Drug Des Devel Ther. 2009 Sep 21;3:89-101. Pubmed
  5. Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, Capucci A, Cedrone M, Fava C, Intermesoli T, Cambrin GR, Stagno F, Tiribelli M, Amabile M, Luatti S, Poerio A, Soverini S, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M: Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood. 2009 Dec 3;114(24):4933-8. Epub 2009 Oct 12. Pubmed

2. Mast/stem cell growth factor receptor Kit

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Mast/stem cell growth factor receptor Kit P10721 Details

References:

  1. Guo T, Agaram NP, Wong GC, Hom G, D’Adamo D, Maki RG, Schwartz GK, Veach D, Clarkson BD, Singer S, DeMatteo RP, Besmer P, Antonescu CR: Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res. 2007 Aug 15;13(16):4874-81. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Tanaka C, Yin OQ, Smith T, Sethuraman V, Grouss K, Galitz L, Harrell R, Schran H: Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants. J Clin Pharmacol. 2011 Jan;51(1):75-83. Epub 2010 Aug 11. Pubmed
  2. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA: Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87. Epub 2010 Sep 1. Pubmed
  3. Yin OQ, Gallagher N, Tanaka C, Fisher D, Sethuraman V, Zhou W, Lin TH, Heuman D, Schran H: Effects of hepatic impairment on the pharmacokinetics of nilotinib: an open-label, single-dose, parallel-group study. Clin Ther. 2009;31 Pt 2:2459-69. Pubmed
  4. Deremer DL, Ustun C, Natarajan K: Nilotinib: a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Clin Ther. 2008 Nov;30(11):1956-75. Pubmed

2. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA: Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87. Epub 2010 Sep 1. Pubmed
  2. Deremer DL, Ustun C, Natarajan K: Nilotinib: a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Clin Ther. 2008 Nov;30(11):1956-75. Pubmed

3. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Yin OQ, Gallagher N, Fischer D, Zhao L, Zhou W, Leroy E, Golor G, Schran H: Effects of nilotinib on single-dose warfarin pharmacokinetics and pharmacodynamics: a randomized, single-blind, two-period crossover study in healthy subjects. Clin Drug Investig. 2011;31(3):169-7http://www.drugbank.ca/lims/molecules/45129. doi: 10.2165/11538700-000000000-00000. Pubmed
  2. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA: Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87. Epub 2010 Sep 1. Pubmed

4. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA: Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87. Epub 2010 Sep 1. Pubmed
  2. Deremer DL, Ustun C, Natarajan K: Nilotinib: a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Clin Ther. 2008 Nov;30(11):1956-75. Pubmed

5. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA: Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87. Epub 2010 Sep 1. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X, Chen ZS: Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol. 2009 Jul 15;78(2):153-61. Epub 2009 Apr 11. Pubmed
  2. Hegedus C, Ozvegy-Laczka C, Apati A, Magocsi M, Nemet K, Orfi L, Keri G, Katona M, Takats Z, Varadi A, Szakacs G, Sarkadi B: Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol. 2009 Oct;158(4):1153-64. Epub 2009 Sep 28. Pubmed
  3. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA: Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87. Epub 2010 Sep 1. Pubmed

2. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X, Chen ZS: Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol. 2009 Jul 15;78(2):153-61. Epub 2009 Apr 11. Pubmed
  2. Hegedus C, Ozvegy-Laczka C, Apati A, Magocsi M, Nemet K, Orfi L, Keri G, Katona M, Takats Z, Varadi A, Szakacs G, Sarkadi B: Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol. 2009 Oct;158(4):1153-64. Epub 2009 Sep 28. Pubmed
  3. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA: Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87. Epub 2010 Sep 1. Pubmed

3. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA: Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011 Feb 24;117(8):e75-87. Epub 2010 Sep 1. Pubmed

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Drug created on October 20, 2007 03:39 / Updated on September 16, 2013 17:26