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Details

Stereochemistry ACHIRAL
Molecular Formula C26H29Cl2N5O3.2H2O
Molecular Weight 566.477
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of BOSUTINIB DIHYDRATE

SMILES

O.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=APHLBYGUSLJFNE-UHFFFAOYSA-N
InChI=1S/C26H29Cl2N5O3.2H2O/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);2*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
Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity.
2001 Nov 8
Structural insights into the ATP binding pocket of the anaplastic lymphoma kinase by site-directed mutagenesis, inhibitor binding analysis, and homology modeling.
2006 Sep 21
Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec, Gleevectrade mark).
2008 Feb
Beyond dose escalation: clinical options for relapse or resistance in chronic myelogenous leukemia.
2008 Mar
AXL is a potential target for therapeutic intervention in breast cancer progression.
2008 Mar 15
P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia.
2008 Oct 1
Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generation.
2008 Sep
Standard management of patients with chronic myeloid leukemia.
2009
Improving Response Rates to EGFR-Targeted Therapies for Head and Neck Squamous Cell Carcinoma: Candidate Predictive Biomarkers and Combination Treatment with Src Inhibitors.
2009
Second-generation tyrosine kinase inhibitors in the post-transplant period in patients with chronic myeloid leukemia or Philadelphia-positive acute lymphoblastic leukemia.
2009
[Synthesis and biological evaluation of 3-quinolinecarbonitrile-7-amide derivatives].
2009 Aug
Neuroprotective profile of novel SRC kinase inhibitors in rodent models of cerebral ischemia.
2009 Dec
Targeted treatment of imatinib-resistant chronic myeloid leukemia: Focus on dasatinib.
2009 Feb 18
Development of novel tyrosine kinase inhibitors for treatment of imatinib-resistant CML patients.
2009 Jul
Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia.
2009 Jul 9
Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts.
2009 Jun
Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma.
2009 Jun
Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells.
2009 Mar
Danusertib (formerly PHA-739358)--a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor.
2010
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
SRC: a century of science brought to the clinic.
2010 Aug
Novel dual Src/Abl inhibitors for hematologic and solid malignancies.
2010 Aug
MASPECTRAS 2: An integration and analysis platform for proteomic data.
2010 Jul
Src inhibitors in lung cancer: current status and future directions.
2010 Jul 1
Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins.
2010 Jul 21
Synthesis of bosutinib from 3-methoxy-4-hydroxybenzoic acid.
2010 Jun 11
New developments in tyrosine kinase inhibitor therapy for newly diagnosed chronic myeloid leukemia.
2010 Mar 15
Optimization of 7-alkene-3-quinolinecarbonitriles as Src kinase inhibitors.
2010 May 1
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
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
2011 Oct 30
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 Thu Jul 06 23:46:14 UTC 2023
Edited
by admin
on Thu Jul 06 23:46:14 UTC 2023
Record UNII
8897ZFQ8MU
Record Status Validated (UNII)
Record Version
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Name Type Language
BOSUTINIB DIHYDRATE
Common Name English
3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-, hydrate (1:2)
Systematic Name English
Code System Code Type Description
SMS_ID
300000046961
Created by admin on Thu Jul 06 23:46:15 UTC 2023 , Edited by admin on Thu Jul 06 23:46:15 UTC 2023
PRIMARY
FDA UNII
8897ZFQ8MU
Created by admin on Thu Jul 06 23:46:14 UTC 2023 , Edited by admin on Thu Jul 06 23:46:14 UTC 2023
PRIMARY
PUBCHEM
139203020
Created by admin on Thu Jul 06 23:46:14 UTC 2023 , Edited by admin on Thu Jul 06 23:46:14 UTC 2023
PRIMARY
Related Record Type Details
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ACTIVE MOIETY