Details
Stereochemistry | ACHIRAL |
Molecular Formula | C26H29Cl2N5O3 |
Molecular Weight | 530.446 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
COC1=C(Cl)C=C(Cl)C(NC2=C(C=NC3=CC(OCCCN4CCN(C)CC4)=C(OC)C=C23)C#N)=C1
InChI
InChIKey=UBPYILGKFZZVDX-UHFFFAOYSA-N
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)
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 Date2012 |
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 |
---|---|---|
SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. | 2003 Jan 15 |
|
SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. | 2007 Jan |
|
NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. | 2007 Nov 14 |
|
Novel agents in CML therapy: tyrosine kinase inhibitors and beyond. | 2008 |
|
The chemistry of multi-protic drugs Part 1: a potentiometric, multi-wavelength UV and NMR pH titrimetric study of the micro-speciation of SKI-606. | 2008 Jun 9 |
|
Characterization of compound 584, an Abl kinase inhibitor with lasting effects. | 2008 May |
|
Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generation. | 2008 Sep |
|
The next generation of therapies for chronic myeloid leukemia. | 2009 |
|
Second-generation tyrosine kinase inhibitors in the post-transplant period in patients with chronic myeloid leukemia or Philadelphia-positive acute lymphoblastic leukemia. | 2009 |
|
Dasatinib in chronic myeloid leukemia: a review. | 2009 Apr |
|
[Synthesis and biological evaluation of 3-quinolinecarbonitrile-7-amide derivatives]. | 2009 Aug |
|
Fyn kinase activity is required for normal organization and functional polarity of the mouse oocyte cortex. | 2009 Sep |
|
Bosutinib. | 2010 |
|
SRC kinase inhibition: targeting bone metastases and tumor growth in prostate and breast cancer. | 2010 Apr |
|
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 |
|
Optimization of 7-alkene-3-quinolinecarbonitriles as Src kinase inhibitors. | 2010 May 1 |
|
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. | 2010 Nov 24 |
|
Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers. | 2010 Nov 30 |
|
Comprehensive analysis 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 |
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.
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WHO-ATC |
L01XE14
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FDA ORPHAN DRUG |
274808
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EU-Orphan Drug |
EU/3/10/762
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NDF-RT |
N0000175605
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NBK547951
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WHO-VATC |
QL01XE14
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NCI_THESAURUS |
C155700
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N0000185503
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C471992
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m2627
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DB06616
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BOSUTINIB
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380843-75-4
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ACTIVE MOIETY
METABOLITE INACTIVE (PARENT)
PARENT (METABOLITE INACTIVE)
PARENT (METABOLITE INACTIVE)
SALT/SOLVATE (PARENT)
SALT/SOLVATE (PARENT)
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