BOSUTINIB

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

Structure Search

SMILES

COC1=CC(NC2=C(C=NC3=CC(OCCCN4CCN(C)CC4)=C(OC)C=C23)C#N)=C(Cl)C=C1Cl

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)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203341s005lbl.pdf
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Proto-oncogene tyrosine-protein kinase Src 8 Target ID: P12931 Gene ID: 6714.0 Gene Symbol: SRC Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203341s005lbl.pdf	Inhibitor 8504		1.2 nM [IC50]
Tyrosine-protein kinase ABL1 7 Target ID: P00519 Gene ID: 25.0 Gene Symbol: ABL1 Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203341s005lbl.pdf	Inhibitor 8504		1.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Leukemia, myelogenous, chronic, BCR-ABL positive 4 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf	Primary		Approved 8583	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 2012

C_max

Value	Dose	Analyte	Population
273 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
190 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
76.6 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	300 mg 1 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
95.4 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
19.6 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
6.9 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	50 mg 1 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
4.89 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
17 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
43.1 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
63.7 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
117 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
125 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
206 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
200 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
200 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf	500 mg 1 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED
216 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: HIGH-FAT
125 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED
278.12 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	600 mg 1 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
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

AUC

Value	Dose	Analyte	Population
3580 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2900 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1170 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	300 mg 1 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1670 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
329 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
114 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	50 mg 1 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
129 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
284 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
920 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
1200 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2340 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2950 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
4300 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
3650 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
3650 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf	500 mg 1 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED
4000 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: HIGH-FAT
2950 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED
4084.7 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	600 mg 1 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
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

T_1/2

Value	Dose	Analyte	Population
23.3 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
19.89 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
19.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	300 mg 1 times / day multiple, oral dose: 300 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
30 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
64.7 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
25.8 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	50 mg 1 times / day multiple, oral dose: 50 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
12.9 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
18.6 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
20.79 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
17.1 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
18.6 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
21.9 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
19.9 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
22.5 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf	500 mg 1 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED
33.8 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: HIGH-FAT
21.9 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED
15.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	600 mg 1 times / day multiple, oral dose: 600 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
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

F_unbound

Value	Dose	Co-administered	Analyte	Population
4% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf	500 mg 1 times / day multiple, oral dose: 500 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BOSUTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
4% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf	500 mg 1 times / day steady-state, oral dose: 500 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		BOSUTINIB plasma	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf	unhealthy, 18-91 years Health Status: unhealthy Age Group: 18-91 years Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf	Disc. AE: Thrombocytopenia, Elevated liver enzymes... AEs leading to discontinuation/dose reduction: Thrombocytopenia (29 patients) Elevated liver enzymes (17 patients) Neutropenia (11 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf
800 mg single, oral Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	healthy, adult Health Status: healthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf
600 mg 1 times / day steady, oral Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	unhealthy Health Status: unhealthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf

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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf	unhealthy, 18-91 years Health Status: unhealthy Age Group: 18-91 years Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf	unhealthy, 18-91 years Health Status: unhealthy Age Group: 18-91 years Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf	unhealthy, 18-91 years Health Status: unhealthy Age Group: 18-91 years Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000MedR.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252 inducer 1087	substrate 1193 inhibitor 2438 inducer 440	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1741 CYP2C19 2057	P-gp 2052 CYP1A2 1197 CYP2A6 626 CYP2B6 776 CYP2C8 810 CYP2E1 729	CYP1A2 832 CYP2B6 669 CYP2C19 329

Drug as perpetrator

Target	Modality	Activity
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2C19 2141	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	yes [IC50 2 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	yes [Ki 10 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	yes [Ki 27 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	yes [Ki 27 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	major	yes (co-administration study) Comment: ketoconazole increased cmax of bosutinib by 5x, auc by 9x Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2A6 626	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2B6 776	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
CYP2E1 729	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	no
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000ClinPharmR.pdf	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203341Orig1s000PharmR.pdf

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:39112	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:39112
ChemicalBook	CB22673646	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB22673646
eMolecules	31507652	https://www.emolecules.com/cgi-bin/more?vid=31507652
MolPort	MolPort-008-155-956	https://www.molport.com/shop/molecule-link/MolPort-008-155-956
Selleck Chemicals	Bosutinib	http://www.selleckchem.com/products/Bosutinib.html
ZINC	ZINC000022448983	http://zinc15.docking.org/substances/ZINC000022448983

PubMed

Title	Date	PubMed
New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance.	2007 Jan	17292738
Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors.	2007 Sep	17721511
Targeted drugs in chronic myeloid leukemia.	2008	19075651
Gateways to clinical trials.	2008 Apr	18597009
Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec, Gleevectrade mark).	2008 Feb	18728706
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	18314291
AXL is a potential target for therapeutic intervention in breast cancer progression.	2008 Mar 15	18339872
Targeted treatment of imatinib-resistant chronic myeloid leukemia: Focus on dasatinib.	2009 Feb 18	20616897
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	19920908
New mechanisms of resistance in Philadelphia chromosome acute lymphoblastic leukemia.	2009 Jun	21082971
Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma.	2009 Jun	19434004
Bosutinib: a dual SRC/ABL kinase inhibitor for the treatment of chronic myeloid leukemia.	2009 Oct	21083014
Efficacy of dasatinib for the treatment of intractable chronic myeloid leukemia.	2010	22282699
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	20862378
[Development of ABL tyrosine kinase inhibitors].	2010 Aug	20805664
SRC: a century of science brought to the clinic.	2010 Aug	20689754
Optimizing combination therapies with existing and future CML drugs.	2010 Aug 23	20808800
Src inhibitors in lung cancer: current status and future directions.	2010 Jul 1	20630825
Gene expression analysis after receptor tyrosine kinase activation reveals new potential melanoma proteins.	2010 Jul 21	20663135
The dual kinase complex FAK-Src as a promising therapeutic target in cancer.	2010 Jun 24	20616959
Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission.	2010 Nov 18	21087500
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574
First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib.	2010 Nov 26	21108851
Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers.	2010 Nov 30	21152443
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.	2011 Oct 30	22037377
LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFα expression and receptor tyrosine kinase signaling.	2012 Mar 1	22241084
Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia.	2012 Sep	23098112
Development and validation of a high-throughput intrinsic ATPase activity assay for the discovery of MEKK2 inhibitors.	2013 Apr	23134735

Patents

Sample Use Guides

In Vivo Use Guide

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

Bosutinib potently inhibits Src-dependent cell proliferation with an IC50 of 100 nM.

Name

Type

Language

SK-606

Preferred Name

English

BOSUTINIB

Official Name

English

BOSUTINIB [USAN]

Common Name

English

BOSULIF

Common Name

English

BOSUTINIB [MI]

Common Name

English

BOSUTINIB [MART.]

Common Name

English

3-QUINOLINECARBONITRILE, 4-((2,4-DICHLORO-5-METHOXYPHENYL)AMINO)-6-METHYL-1-PIPERAZINYL)PROPOXY)-

Common Name

English

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile

Systematic Name

English

BOSUTINIB [VANDF]

Common Name

English

SKI-606

Code

English

bosutinib [INN]

Common Name

English

Bosutinib [WHO-DD]

Common Name

English

Classification Tree Code System Code

WHO-ATC

L01XE14