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
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
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 |
DescriptionCurator'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
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
Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=25635231
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)
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
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
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | BOSULIF Approved UseIndicated 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 Date1.33392957E12 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
62.1 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27113346 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27113346 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1150 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27113346 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27113346 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
39.1 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27113346 |
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 EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27113346 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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
Dose | Population | Adverse 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) Sources: Elevated liver enzymes (17 patients) Neutropenia (11 patient) |
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
AE | Significance | Dose | Population |
---|---|---|---|
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: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
yes [IC50 2 uM] | ||||
yes [Ki 10 uM] | ||||
yes [Ki 27 uM] | ||||
yes [Ki 27 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major | yes (co-administration study) Comment: ketoconazole increased cmax of bosutinib by 5x, auc by 9x |
|||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
yes |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
Kinase inhibitors in chronic myelogenous leukemia. | 2006 May |
|
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 |
|
NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. | 2007 Nov 14 |
|
Characterization of compound 584, an Abl kinase inhibitor with lasting effects. | 2008 May |
|
P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia. | 2008 Oct 1 |
|
Severe toxicity of skin rash, fever and diarrhea associated with imatinib: case report and review of skin toxicities associated with tyrosine kinase inhibitors. | 2009 Feb 6 |
|
Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. | 2009 Jul 9 |
|
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 |
|
Novel dual Src/Abl inhibitors for hematologic and solid malignancies. | 2010 Aug |
|
MASPECTRAS 2: An integration and analysis platform for proteomic data. | 2010 Jul |
|
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 |
|
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 |
|
Standard treatment of Ph+ CML in 2010: how, when and where not to use what BCR/ABL1 kinase inhibitor? | 2010 Oct |
|
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 |
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
In Vitro Use Guide
Sources: http://www.ncbi.nlm.nih.gov/pubmed/?term=11689083
Bosutinib potently inhibits Src-dependent cell proliferation with an IC50 of 100 nM.
Substance Class |
Chemical
Created
by
admin
on
Edited
Fri Dec 15 15:35:41 UTC 2023
by
admin
on
Fri Dec 15 15:35:41 UTC 2023
|
Record UNII |
844ZJE6I55
|
Record Status |
Validated (UNII)
|
Record Version |
|
-
Download
Name | Type | Language | ||
---|---|---|---|---|
|
Common Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Code | English | ||
|
Systematic Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Common Name | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
NCI_THESAURUS |
C155700
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
SUB120769
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
DTXSID20238722
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
DBSALT002837
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
11990828
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
844ZJE6I55
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
918639-08-4
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
100000144021
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
68533
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
CHEMBL288441
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
844ZJE6I55
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | |||
|
1314319
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY | RxNorm | ||
|
C154440
Created by
admin on Fri Dec 15 15:35:41 UTC 2023 , Edited by admin on Fri Dec 15 15:35:41 UTC 2023
|
PRIMARY |
Related Record | Type | Details | ||
---|---|---|---|---|
|
ANHYDROUS->SOLVATE | |||
|
PARENT -> SALT/SOLVATE |
Related Record | Type | Details | ||
---|---|---|---|---|
|
ACTIVE MOIETY |