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
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
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 |
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 |
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 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. | 2006 Feb 15 |
|
[Novel anti-CML agents beyond imatinib]. | 2007 Jun |
|
Tailoring tyrosine kinase inhibitor therapy to tackle specific BCR-ABL1 mutant clones. | 2008 Aug |
|
Targeted therapy in chronic myeloid leukemia. | 2008 Jan |
|
New mechanisms of resistance in Philadelphia chromosome acute lymphoblastic leukemia. | 2009 Jun |
|
Acid elution and one-dimensional shotgun analysis on an Orbitrap mass spectrometer: an application to drug affinity chromatography. | 2009 Oct |
|
Advances in the biology and therapy of patients with chronic myeloid leukaemia. | 2009 Sep |
|
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 |
|
Tyrosine kinase inhibitors: the first decade. | 2010 Apr |
|
[Development of ABL tyrosine kinase inhibitors]. | 2010 Aug |
|
SRC: a century of science brought to the clinic. | 2010 Aug |
|
Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins. | 2010 Jul 21 |
|
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 |
|
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. | 2010 Nov 24 |
|
[SRC kinases in tumor therapy]. | 2010 Oct |
|
Comprehensive analysis 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 |
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
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admin
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Edited
Sat Dec 16 18:30:02 GMT 2023
by
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on
Sat Dec 16 18:30:02 GMT 2023
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Record UNII |
8897ZFQ8MU
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Record Status |
Validated (UNII)
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Record Version |
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Created by
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8897ZFQ8MU
Created by
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