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Details

Stereochemistry ACHIRAL
Molecular Formula C26H29Cl2N5O3.H2O
Molecular Weight 548.461
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of BOSUTINIB MONOHYDRATE

SMILES

O.COC1=C(Cl)C=C(Cl)C(NC2=C(C=NC3=CC(OCCCN4CCN(C)CC4)=C(OC)C=C23)C#N)=C1

InChI

InChIKey=BXPOSPOKHGNMEP-UHFFFAOYSA-N
InChI=1S/C26H29Cl2N5O3.H2O/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);1H2

HIDE SMILES / InChI

Molecular Formula C26H29Cl2N5O3
Molecular Weight 530.446
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula H2O
Molecular Weight 18.0153
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment: description was created based on several sources, including http://www.drugdevelopment-technology.com/projects/bosutinib-leukaemia/; http://www.pharmacodia.com/yaodu/html/v1/chemicals/d6bcb486f72ae7b5dc68b5b7df7ec887.html

Bosutinib (trade name Bosulif) originally synthesized by Wyeth, it is being developed by Pfizer. Bosutinib received US FDA and EU European Medicines Agency approval on September 4, 2012 and 27 March 2013 respectively for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy. Bosutinib is a synthetic quinolone derivative and dual kinase inhibitor that targets both Abl and Src kinases with potential antineoplastic activity. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis. Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors. Abl kinase is upregulated in the presence of the abnormal Bcr-abl fusion protein which is commonly associated with chronic myeloid leukemia (CML). Overexpression of specific Src kinases is also associated with the imatinib-resistant CML phenotype.

CNS Activity

Curator's Comment: Bosutinib penetrates the brain, inhibits Abl activity and induces autophagic clearance of α-Synuclein and p-Tau in A53T mice and lentiviral gene transfer models. In another study it was shown that although bosutinib does show wide tissue distribution it but does not cross the blood brain barrier (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2014_bosulif_152211-eng.php)

Originator

Curator's Comment: The drug was originally developed by Wyeth Pharmaceuticals, which was taken over by Pfizer in October 2009.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: P12931
Gene ID: 6714.0
Gene Symbol: SRC
Target Organism: Homo sapiens (Human)
1.2 nM [IC50]
Target ID: P00519
Gene ID: 25.0
Gene Symbol: ABL1
Target Organism: Homo sapiens (Human)
1.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
BOSULIF

Approved Use

Indicated for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.

Launch Date

1.33392957E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
62.1 ng/mL
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FASTED
88 ng/mL
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
200 ng/mL
500 mg 1 times / day multiple, oral
dose: 500 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
125 ng/mL
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
182.425 ng/mL
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
200 ng/mL
500 mg 1 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
216 ng/mL
800 mg single, oral
dose: 800 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
1150 ng × h/mL
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FASTED
1768 ng × h/mL
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
3650 ng × h/mL
500 mg 1 times / day multiple, oral
dose: 500 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
2950 ng × h/mL
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
3160 ng × h/mL
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
3650 ng × h/mL
500 mg 1 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
4000 ng × h/mL
800 mg single, oral
dose: 800 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
39.1 h
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FASTED
32.4 h
400 mg single, oral
dose: 400 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
21.9 h
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
21.4 h
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
22.5 h
500 mg 1 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
33.8 h
800 mg single, oral
dose: 800 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: UNKNOWN
food status: HIGH-FAT
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
4%
500 mg 1 times / day multiple, oral
dose: 500 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
4%
500 mg 1 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
BOSUTINIB unknown
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: FED
Doses

Doses

DosePopulationAdverse events​
500 mg 1 times / day steady, oral
Recommended
Dose: 500 mg, 1 times / day
Route: oral
Route: steady
Dose: 500 mg, 1 times / day
Sources:
unhealthy, 18-91 years
n = 571
Health Status: unhealthy
Age Group: 18-91 years
Sex: M+F
Population Size: 571
Sources:
Disc. AE: Thrombocytopenia, Elevated liver enzymes...
AEs leading to
discontinuation/dose reduction:
Thrombocytopenia (29 patients)
Elevated liver enzymes (17 patients)
Neutropenia (11 patient)
Sources:
800 mg single, oral
Dose: 800 mg
Route: oral
Route: single
Dose: 800 mg
Sources:
healthy, adult
n = 5
Health Status: healthy
Age Group: adult
Population Size: 5
Sources:
600 mg 1 times / day steady, oral
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy
n = 2
Health Status: unhealthy
Condition: advanced malignant solid tumors
Population Size: 2
Sources:
AEs

AEs

AESignificanceDosePopulation
Neutropenia 11 patient
Disc. AE
500 mg 1 times / day steady, oral
Recommended
Dose: 500 mg, 1 times / day
Route: oral
Route: steady
Dose: 500 mg, 1 times / day
Sources:
unhealthy, 18-91 years
n = 571
Health Status: unhealthy
Age Group: 18-91 years
Sex: M+F
Population Size: 571
Sources:
Elevated liver enzymes 17 patients
Disc. AE
500 mg 1 times / day steady, oral
Recommended
Dose: 500 mg, 1 times / day
Route: oral
Route: steady
Dose: 500 mg, 1 times / day
Sources:
unhealthy, 18-91 years
n = 571
Health Status: unhealthy
Age Group: 18-91 years
Sex: M+F
Population Size: 571
Sources:
Thrombocytopenia 29 patients
Disc. AE
500 mg 1 times / day steady, oral
Recommended
Dose: 500 mg, 1 times / day
Route: oral
Route: steady
Dose: 500 mg, 1 times / day
Sources:
unhealthy, 18-91 years
n = 571
Health Status: unhealthy
Age Group: 18-91 years
Sex: M+F
Population Size: 571
Sources:
OverviewDrug as perpetrator​Drug as victimTox targets

Tox targets

PubMed

PubMed

TitleDatePubMed
The next generation of therapies for chronic myeloid leukemia.
2009
Standard management of patients with chronic myeloid leukemia.
2009
[Synthesis and biological evaluation of 3-quinolinecarbonitrile-7-amide derivatives].
2009 Aug
Targeted treatment of imatinib-resistant chronic myeloid leukemia: Focus on dasatinib.
2009 Feb 18
Targeted treatment of chronic myeloid leukemia: role of imatinib.
2009 Feb 18
The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2).
2009 Feb 24
Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia.
2009 Jul 9
New mechanisms of resistance in Philadelphia chromosome acute lymphoblastic leukemia.
2009 Jun
Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts.
2009 Jun
Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome-positive acute lymphoblastic leukaemia.
2009 Jun
Bosutinib: a dual SRC/ABL kinase inhibitor for the treatment of chronic myeloid leukemia.
2009 Oct
New targets for Ph+ leukaemia therapy.
2009 Sep
Advances in the biology and therapy of patients with chronic myeloid leukaemia.
2009 Sep
Efficacy of dasatinib for the treatment of intractable chronic myeloid leukemia.
2010
Locking Src/Abl Tyrosine Kinase Activities Regulate Cell Differentiation and Invasion of Human Cervical Cancer Cells Expressing E6/E7 Oncoproteins of High-Risk HPV.
2010
Danusertib (formerly PHA-739358)--a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor.
2010
Bosutinib.
2010
Tyrosine kinase inhibitors: the first decade.
2010 Apr
Lung adenocarcinoma cells floating in lymphatic vessels resist anoikis by expressing phosphorylated Src.
2010 Apr
SRC kinase inhibition: targeting bone metastases and tumor growth in prostate and breast cancer.
2010 Apr
Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy.
2010 Apr 12
[Development of ABL tyrosine kinase inhibitors].
2010 Aug
SRC: a century of science brought to the clinic.
2010 Aug
Novel dual Src/Abl inhibitors for hematologic and solid malignancies.
2010 Aug
Detection of centrosome aberrations in disease-unrelated cells from patients with tumor treated with tyrosine kinase inhibitors.
2010 Aug
A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl.
2010 Aug 12
Optimizing combination therapies with existing and future CML drugs.
2010 Aug 23
MASPECTRAS 2: An integration and analysis platform for proteomic data.
2010 Jul
Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia.
2010 Jul
Src inhibitors in lung cancer: current status and future directions.
2010 Jul 1
Advances in targeting SRC in the treatment of breast cancer and other solid malignancies.
2010 Jul 15
Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins.
2010 Jul 21
Synergistic activity of the Src/Abl inhibitor bosutinib in combination with imatinib.
2010 Jun
Synthesis of bosutinib from 3-methoxy-4-hydroxybenzoic acid.
2010 Jun 11
The dual kinase complex FAK-Src as a promising therapeutic target in cancer.
2010 Jun 24
Inhibition of Ser/Thr phosphatases induces capacitation-associated signaling in the presence of Src kinase inhibitors.
2010 Mar 12
New developments in tyrosine kinase inhibitor therapy for newly diagnosed chronic myeloid leukemia.
2010 Mar 15
SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis.
2010 May
Optimization of 7-alkene-3-quinolinecarbonitriles as Src kinase inhibitors.
2010 May 1
Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission.
2010 Nov 18
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
2010 Nov 24
First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib.
2010 Nov 26
Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers.
2010 Nov 30
[SRC kinases in tumor therapy].
2010 Oct
Standard treatment of Ph+ CML in 2010: how, when and where not to use what BCR/ABL1 kinase inhibitor?
2010 Oct
Comprehensive analysis of kinase inhibitor selectivity.
2011 Oct 30
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
2011 Oct 30
LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFα expression and receptor tyrosine kinase signaling.
2012 Mar 1
Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia.
2012 Sep
Development and validation of a high-throughput intrinsic ATPase activity assay for the discovery of MEKK2 inhibitors.
2013 Apr
Patents

Sample Use Guides

Recommended Dose: 500 mg orally once daily with food. Consider dose escalation to 600 mg daily in patients who do not reach complete hematologic response by week 8 or complete cytogenetic response by week 12 and do not have Grade 3 or greater adverse reactions.
Route of Administration: Oral
Bosutinib potently inhibits Src-dependent cell proliferation with an IC50 of 100 nM.
Substance Class Chemical
Created
by admin
on Wed Jul 05 23:04:53 UTC 2023
Edited
by admin
on Wed Jul 05 23:04:53 UTC 2023
Record UNII
844ZJE6I55
Record Status Validated (UNII)
Record Version
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Name Type Language
BOSUTINIB MONOHYDRATE
ORANGE BOOK  
Common Name English
BOSUTINIB MONOHYDRATE [ORANGE BOOK]
Common Name English
BOSUTINIB (AS MONOHYDRATE) [EMA EPAR]
Common Name English
SKI-606 MONOHYDRATE
Code English
3-QUINOLINECARBONITRILE, 4-((2,4-DICHLORO-5-METHOXYPHENYL)AMINO)-6-METHOXY-7-(3-(4-METHYL-1-PIPERAZINYL)PROPOXY)-, HYDRATE (1:1)
Systematic Name English
BOSUTINIB (AS MONOHYDRATE)
EMA EPAR  
Common Name English
BOSUTINIB HYDRATE [JAN]
Common Name English
BOSUTINIB HYDRATE
JAN  
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C155700
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
Code System Code Type Description
EVMPD
SUB120769
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
EPA CompTox
DTXSID20238722
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
DRUG BANK
DBSALT002837
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
PUBCHEM
11990828
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
DAILYMED
844ZJE6I55
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
CAS
918639-08-4
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
SMS_ID
100000144021
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
CHEBI
68533
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
ChEMBL
CHEMBL288441
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
FDA UNII
844ZJE6I55
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
RXCUI
1314319
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY RxNorm
NCI_THESAURUS
C154440
Created by admin on Wed Jul 05 23:04:53 UTC 2023 , Edited by admin on Wed Jul 05 23:04:53 UTC 2023
PRIMARY
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ANHYDROUS->SOLVATE
PARENT -> SALT/SOLVATE
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ACTIVE MOIETY