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Identification
NameBosutinib
Accession NumberDB06616
Typesmall molecule
Groupsapproved
Description

Bosutinib is a Bcr-Abl kinase inhibitor for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). Compared to other tyrosine kinase inhibitors, it has a more favourable hematologic toxicity profile. FDA approved on September 4, 2012.

Structure
Thumb
Synonyms
SynonymLanguageCode
Bosulif®Not AvailableNot Available
Bosutinib MonohydrateNot AvailableNot Available
SKI-606Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
Bosulif Pfizer
Brand mixturesNot Available
CategoriesNot Available
CAS number380843-75-4
WeightAverage: 530.446
Monoisotopic: 529.164745233
Chemical FormulaC26H29Cl2N5O3
InChI KeyInChIKey=UBPYILGKFZZVDX-UHFFFAOYSA-N
InChI
InChI=1S/C26H29Cl2N5O3/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27/h11-14,16H,4-10H2,1-3H3,(H,30,31)
IUPAC Name
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile
SMILES
COC1=CC(NC2=C(C=NC3=CC(OCCCN4CCN(C)CC4)=C(OC)C=C23)C#N)=C(Cl)C=C1Cl
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassQuinolines and Derivatives
SubclassAminoquinolines and Derivatives
Direct parentAminoquinolines and Derivatives
Alternative parentsHydroxyquinolines; Anisoles; Dichlorobenzenes; Alkyl Aryl Ethers; Aminopyridines and Derivatives; Diazinanes; Piperazines; Aryl Chlorides; Tertiary Amines; Polyamines; Nitriles; Secondary Amines; Organochlorides
Substituents1,3-dichlorobenzene; phenol ether; anisole; aminopyridine; chlorobenzene; alkyl aryl ether; piperazine; benzene; pyridine; aryl halide; aryl chloride; 1,4-diazinane; tertiary amine; carbonitrile; nitrile; ether; polyamine; secondary amine; organochloride; organonitrogen compound; organohalogen; amine
Classification descriptionThis compound belongs to the aminoquinolines and derivatives. These are organic compounds containing an amino group attached to a quinoline ring system.
Pharmacology
IndicationTreatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy in adult patients.
PharmacodynamicsNot Available
Mechanism of actionBosutinib is a tyrosine kinase inhibitor. Although it is able to inhibit several tyrosine kinases such as Src, Lyn, and Hck, which are members of the Src-family of kinases, its primary target is the Bcr-Abl kinase. The Bcr-Abl gene is a chimeric oncogene created from the fusion of the breakpoint-cluster (Bcr) gene and Abelson (Abl) tyrosine gene. This chromosomal abnormality results in the formation of what is commonly known as the Philadelphia chromosome or Philadelphia translocation. The Bcr-Abl gene expresses a particular kinase that promotes the progression of CML. A decrease in the growth and size of the CML tumour has been observed following administration of bosutinib. Bosutinib did not inhibit the T315I and V299L mutant cells.
AbsorptionFood increase the exposure of bosutinib. Tmax, single dose, cancer patients, fed-state = 4-6 hours; After 15 daily doses of bosutinib 500 mg with food in CML patients, the pharmacokinetic parameters are as follows: Cmax = 200 ng/mL; AUC = 3650 ng∙h/mL
Volume of distribution

Apparent volume of distribution = 6080 ± 1230 L.

Protein binding94% bound to human plasma proteins in vitro. 96% bound to human plasma proteins in healthy subjects ex vivo. Extent of protein binding is not concentration-dependent.
Metabolism

Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive.

Route of eliminationWhen given a single oral dose, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine.
Half lifeTerminal phase elimination half-life, single oral dose, fed-state = 22.5 hours
Clearance

Mean clearance (CL/F), single oral dose, fed-state = 189 L/h

ToxicityMost common adverse reactions (incidence greater than 20%) are diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue. Because bosutinib is not an inhibitor of c-KIT or PDGF receptor, it has less hematologic toxicities.
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 + 0.9823
Blood Brain Barrier + 0.9272
Caco-2 permeable + 0.6542
P-glycoprotein substrate Substrate 0.7601
P-glycoprotein inhibitor I Inhibitor 0.8409
P-glycoprotein inhibitor II Inhibitor 0.9108
Renal organic cation transporter Inhibitor 0.5663
CYP450 2C9 substrate Non-substrate 0.854
CYP450 2D6 substrate Non-substrate 0.6953
CYP450 3A4 substrate Substrate 0.6987
CYP450 1A2 substrate Inhibitor 0.5606
CYP450 2C9 substrate Non-inhibitor 0.7372
CYP450 2D6 substrate Non-inhibitor 0.5136
CYP450 2C19 substrate Non-inhibitor 0.5725
CYP450 3A4 substrate Inhibitor 0.5
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7021
Ames test AMES toxic 0.5922
Carcinogenicity Non-carcinogens 0.8869
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.4201 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.6147
hERG inhibition (predictor II) Inhibitor 0.7754
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral100 mg, 500 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States60020082012-09-042018-03-27
United States74171482012-09-042026-01-23
United States77676782012-09-042026-11-23
United States79196252012-09-042025-12-11
United StatesRE423762012-09-042019-09-24
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility9.50e-03 g/lALOGPS
logP4.87ALOGPS
logP4.09ChemAxon
logS-4.8ALOGPS
pKa (strongest acidic)15.48ChemAxon
pKa (strongest basic)8.43ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count8ChemAxon
hydrogen donor count1ChemAxon
polar surface area82.88ChemAxon
rotatable bond count9ChemAxon
refractivity142.12ChemAxon
polarizability56.14ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. http://en.wikipedia.org/wiki/Philadelphia_chromosome
  2. FDA label
  3. Amsberg GK, Schafhausen P: Bosutinib in the management of chronic myelogenous leukemia. Biologics. 2013;7:115-22. doi: 10.2147/BTT.S30182. Epub 2013 May 6. Pubmed
  4. Keller-V Amsberg G, Brummendorf TH: Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia. Expert Rev Anticancer Ther. 2012 Sep;12(9):1121-7. doi: 10.1586/era.12.84. Pubmed
External Links
ResourceLink
KEGG DrugD03252
ChEBI39112
ChEMBLCHEMBL288441
RxListhttp://www.rxlist.com/bosulif-drug.htm
Drugs.comhttp://www.drugs.com/cdi/bosutinib.html
WikipediaBosutinib
ATC CodesL01XE14
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(326 KB)
MSDSshow(97.1 KB)
Interactions
Drug Interactions
Drug
AbirateroneAbiraterone increases levels by P-glycoprotein (MDR1) efflux transporter. Consider alternate therapy.
CrizotinibStrong CYP3A4 inhibitors may increase levels of crizotinib. Consider alternative therapy.
DigoxinBosutinib is a substrate and inhibitor of p-glycoprotein (p-gp) and may increase levels of other p-gp substrates.
EtravirineBosutinib, when used concomitantly with etravirine, may experience a decrease in serum concentration. It is recommended to avoid this combination.
KetoconazoleStrong CYP3A4 inhibitors may increase levels of bosutinib. Monitor concomitant therapy closely.
LansoprazoleConcomitant lansoprazole (PPI) decreased bosutinib Cmax by 46% and AUC by 26% compared to bosutinib alone. Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure. Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours.
RifampicinStrong CYP3A4 inducers may decrease levels of bosutinib. Monitor concomitant therapy closely.
Food Interactions
  • When given with a high fat meal, the Cmax and AUC of bosutinib increased 1.8- and 1.7-fold, respectively.

1. Breakpoint cluster region protein

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Breakpoint cluster region protein P11274 Details

References:

  1. FDA label

2. 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. FDA label

3. Tyrosine-protein kinase Lyn

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Tyrosine-protein kinase Lyn P07948 Details

References:

  1. FDA label

4. Tyrosine-protein kinase HCK

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Tyrosine-protein kinase HCK P08631 Details

References:

  1. FDA label

5. Proto-oncogene tyrosine-protein kinase Src

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Proto-oncogene tyrosine-protein kinase Src P12931 Details

References:

  1. FDA label

6. Cyclin-dependent kinase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cyclin-dependent kinase 2 P24941 Details

References:

  1. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G: Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27. Pubmed

7. Dual specificity mitogen-activated protein kinase kinase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Dual specificity mitogen-activated protein kinase kinase 1 Q02750 Details

References:

  1. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G: Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27. Pubmed

8. Dual specificity mitogen-activated protein kinase kinase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Dual specificity mitogen-activated protein kinase kinase 2 P36507 Details

References:

  1. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G: Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27. Pubmed

9. Mitogen-activated protein kinase kinase kinase 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Mitogen-activated protein kinase kinase kinase 2 Q9Y2U5 Details

References:

  1. Ahmad S, Hughes MA, Johnson GL, Scott JE: Development and validation of a high-throughput intrinsic ATPase activity assay for the discovery of MEKK2 inhibitors. J Biomol Screen. 2013 Apr;18(4):388-99. doi: 10.1177/1087057112466430. Epub 2012 Nov 7. Pubmed

10. Calcium/calmodulin-dependent protein kinase type II subunit gamma

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Calcium/calmodulin-dependent protein kinase type II subunit gamma Q13555 Details

References:

  1. Amsberg GK, Koschmieder S: Profile of bosutinib and its clinical potential in the treatment of chronic myeloid leukemia. Onco Targets Ther. 2013;6:99-106. doi: 10.2147/OTT.S19901. Epub 2013 Mar 4. Pubmed

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. FDA label

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. FDA label

Comments
Drug created on March 19, 2008 10:41 / Updated on September 16, 2013 18:04