Bosutinib

Identification

Summary

Bosutinib is an antineoplastic agent used for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adults with inadequate clinical response to other treatments.

Brand Names

Bosulif

Generic Name

Bosutinib

DrugBank Accession Number

DB06616

Background

Bosutinib is a 7-alkoxy-3-quinolinecarbonitrile that functions as a potent, dual SRC and ABL tyrosine kinase inhibitor indicated for chronic myelogenous leukemia (CML), specifically Philadelphia chromosome-positive (Ph+) CML. Philadelphia chromosome is a hallmark of CML due to the reciprocal translocation t(9;22)(q34;q11), resulting in a BCR-ABL fusion protein.^2,3,5 The first BCR-ABL inhibitor, imatinib, was introduced over a decade ago as a breakthrough in CML management; however, emerging resistance to imatinib poses challenges in achieving remission.⁴ Second-generation BCR-ABL inhibitors like bosutinib inhibit most resistance-conferring BCR-ABL mutations except V299L and T315, thus providing more therapeutic options for patients.^1,4

Bosutinib was first approved by the FDA in 2012 for the treatment of adult chronic, accelerated, or blast-phase Ph+ CML with resistance or intolerance to prior therapy.¹⁰ On September 26, 2023, bosutinib was also approved by the FDA for the treatment of pediatric CML that is newly diagnosed or resistant/intolerant to prior therapy. This approval was based on favorable results obtained from the open-label, randomized, multicenter trial BFORE that showed a significant improvement in major molecular response, defined as a ≤0.1% BCR ABL ratio on an international scale, with bosutinib treatment.¹¹

Type

Small Molecule

Groups

Approved

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Bosutinib (DB06616)

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Weight

Average: 530.446
Monoisotopic: 529.164745233

Chemical Formula

C₂₆H₂₉Cl₂N₅O₃

Synonyms

• 4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)-3-quinolinecarbonitrile
• Bosutinib

External IDs

• SK-606
• SKI 606
• SKI-606

Pharmacology

Indication

Bosutinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia that is newly diagnosed or resistant or intolerant to prior therapy. It is also indicated for the treatment of adult patients with accelerated or blast phase Philadelphia chromosome-positive chronic myelogenous leukemia that is newly diagnosed or resistant or intolerant to prior therapy.⁶

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Associated Conditions

• Accelerated Phase Chronic Myelogenous Leukemia (CML)
• Chronic Phase Chronic Myeloid Leukemia
• Blast phase Chronic myeloid leukemia

Contraindications & Blackbox Warnings

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Pharmacodynamics

A greater likelihood of response and a greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized.⁶

At a single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent.⁶

Mechanism of action

Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells.⁶

Target	Actions	Organism
ATyrosine-protein kinase ABL1	inhibitor	Humans
ATyrosine-protein kinase Lyn	inhibitor	Humans
AProto-oncogene tyrosine-protein kinase Src	inhibitor	Humans
ADual specificity mitogen-activated protein kinase kinase 1	inhibitor	Humans
ADual specificity mitogen-activated protein kinase kinase 2	inhibitor	Humans
AMitogen-activated protein kinase kinase kinase 2	inhibitor	Humans
ACalcium/calmodulin-dependent protein kinase type II subunit gamma	inhibitor	Humans
ATyrosine-protein kinase Fgr	inhibitor	Humans
ATyrosine-protein kinase HCK	inhibitor	Humans
ATyrosine-protein kinase Tec	inhibitor	Humans
ASTE20-like serine/threonine-protein kinase	inhibitor	Humans

Absorption

Bosutinib exhibits dose-proportional increases in C_max and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady-state C_max was 127 ng/mL (31%), C_trough was 68 ng/mL (39%) and AUC was 2370 ng•h/mL (34%) following multiple oral doses of bosutinib 400 mg. Bosutinib steady-state C_max was 171 ng/mL (38%), C_trough was 91 ng/mL (42%) and AUC was 3150 ng•h/mL (38%) following multiple oral doses of bosutinib 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms of bosutinib at the same dose, under fed conditions.⁶

The median bosutinib (minimum, maximum) t_max was 6.0 (6.0, 6.0) hours following oral administration of a single oral dose of bosutinib 500 mg with food. The absolute bioavailability was 34% in healthy subjects.⁶

Bosutinib C_max increased 1.8-fold and AUC increased 1.7-fold when bosutinib tablets were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. Bosutinib C_max increased 1.6-fold and AUC increased 1.5-fold when bosutinib capsules were given with a high-fat meal to healthy subjects compared to administration under fasted conditions. The high-fat meal (800-1000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500-600 fat calories.⁶

Volume of distribution

The mean (SD) apparent bosutinib volume of distribution is 6080 ± 1230 L after an oral dose of 500 mg of bosutinib.⁶

Protein binding

Bosutinib protein binding is 94% in vitro and 96% ex vivo and is independent of concentration.⁶

Metabolism

Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive.

Hover over products below to view reaction partners

• Bosutinib
  • N-desmethylbosutinib
  • Oxydechlorinated bosutinib

Route of elimination

Following a single oral dose of [¹⁴C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose was recovered in urine.⁶

Half-life

The mean (SD) bosutinib terminal phase elimination half-life (t^1/2) was 22.5 ± 1.7 hours following a single oral dose of bosutinib.⁶

Clearance

The mean (SD) apparent clearance was 189 ± 48 L/h following a single oral dose of bosutinib.⁶

Adverse Effects

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Toxicity

In a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on the day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).⁶

In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae and 2 fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively.⁶

Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a rat pre-and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).⁶

Experience with bosutinib overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment.⁶

Bosutinib was not carcinogenic in rats or transgenic mice. The rat 2-year carcinogenicity study was conducted at bosutinib oral doses up to 25 mg/kg in males and 15 mg/kg in females. Exposures at these doses were approximately 1.5 times (males) and 3.1 times (females) the human exposure at the 400 mg dose and 1.2 times (males) and 2.4 times (females) exposure in humans at the 500 mg dose. The 6-month RasH2 transgenic mouse carcinogenicity study was conducted at bosutinib oral doses up to 60 mg/kg.⁶

Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice.⁶

In a rat fertility study, drug-treated males were mated with untreated females or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately 1.5 times and equal to human exposure at the recommended doses of 400 and 500 mg/day, respectively. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 and 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).⁶

Pathways

Pathway	Category
Bosutinib Inhibition of BCR-ABL	Drug action

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Bosutinib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Bosutinib can be increased when combined with Abatacept.
Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Bosutinib.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Bosutinib.
Abrocitinib	The serum concentration of Bosutinib can be increased when it is combined with Abrocitinib.
Acalabrutinib	The serum concentration of Bosutinib can be increased when it is combined with Acalabrutinib.
Acenocoumarol	The serum concentration of Acenocoumarol can be increased when it is combined with Bosutinib.
Acetaminophen	The serum concentration of Bosutinib can be increased when it is combined with Acetaminophen.
Acetazolamide	The serum concentration of Bosutinib can be increased when it is combined with Acetazolamide.
Acetylsalicylic acid	The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Bosutinib.

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Food Interactions

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of bosutinib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of bosutinib.
• Take with food. Coadministration with a high-fat meal may increase the AUC of bosutinib.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Bosutinib monohydrate	844ZJE6I55	918639-08-4	BXPOSPOKHGNMEP-UHFFFAOYSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Bosulif	Tablet, film coated	400 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2017-12-18	Not applicable
Bosulif	Tablet, film coated	100 mg	Oral	Pfizer Europe Ma Eeig	2016-09-08	Not applicable
Bosulif	Tablet	500 mg	Oral	Pfizer Canada Ulc	2014-03-24	Not applicable
Bosulif	Tablet, film coated	400 mg	Oral	Pfizer Europe Ma Eeig	2020-12-16	Not applicable
Bosulif	Tablet, film coated	100 mg/1	Oral	U.S. Pharmaceuticals	2012-09-04	Not applicable
Bosulif	Tablet, film coated	500 mg	Oral	Pfizer Europe Ma Eeig	2016-09-08	Not applicable
Bosulif	Tablet, film coated	500 mg/1	Oral	Pfizer Laboratories Div Pfizer Inc	2012-09-04	Not applicable
Bosulif	Tablet, film coated	400 mg/1	Oral	U.S. Pharmaceuticals	2012-09-04	Not applicable
Bosulif	Tablet	100 mg	Oral	Pfizer Canada Ulc	2014-04-24	Not applicable
Bosulif	Tablet, film coated	100 mg	Oral	Pfizer Europe Ma Eeig	2016-09-08	Not applicable

Categories

ATC Codes

L01EA04 — Bosutinib

• L01EA — BCR-ABL tyrosine kinase inhibitors
• L01E — PROTEIN KINASE INHIBITORS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Amines
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Bcr-Abl Tyrosine Kinase Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C8 Inhibitors (weak)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A4 Inhibitors (weak)
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Heterocyclic Compounds, Fused-Ring
• Immunosuppressive Agents
• Kinase Inhibitor
• Myelosuppressive Agents
• Narrow Therapeutic Index Drugs
• P-glycoprotein inhibitors
• P-glycoprotein substrates
• P-glycoprotein substrates with a Narrow Therapeutic Index
• Protein Kinase Inhibitors
• Tyrosine Kinase Inhibitors

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as 4-aminoquinolines. These are organic compounds containing an amino group attached to the 4-position of a quinoline ring system.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Quinolines and derivatives

Sub Class

Aminoquinolines and derivatives

Direct Parent

4-aminoquinolines

Alternative Parents

Aminophenyl ethers / Methoxyanilines / Phenoxy compounds / Anisoles / Dichlorobenzenes / Methoxybenzenes / Alkyl aryl ethers / Aminopyridines and derivatives / N-methylpiperazines / Aryl chlorides / Heteroaromatic compounds / Trialkylamines / Nitriles / Azacyclic compounds / Secondary amines / Organochlorides / Organopnictogen compounds / Hydrocarbon derivatives

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Substituents

1,3-dichlorobenzene / 1,4-diazinane / 4-aminoquinoline / Alkyl aryl ether / Amine / Aminophenyl ether / Aminopyridine / Aniline or substituted anilines / Anisole / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonitrile / Chlorobenzene / Ether / Halobenzene / Heteroaromatic compound / Hydrocarbon derivative / Methoxyaniline / Methoxybenzene / Monocyclic benzene moiety / N-alkylpiperazine / N-methylpiperazine / Nitrile / Organic nitrogen compound / Organic oxygen compound / Organochloride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Phenol ether / Phenoxy compound / Piperazine / Pyridine / Secondary amine / Tertiary aliphatic amine / Tertiary amine

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

tertiary amino compound, aromatic ether, nitrile, dichlorobenzene, aminoquinoline, N-methylpiperazine (CHEBI:39112)

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

5018V4AEZ0

CAS number

380843-75-4

InChI Key

UBPYILGKFZZVDX-UHFFFAOYSA-N

InChI

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)

IUPAC Name

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

SMILES

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

References

Synthesis Reference

http://www.ncbi.nlm.nih.gov/pubmed/23674887

General References

1. Amsberg GK, Schafhausen P: Bosutinib in the management of chronic myelogenous leukemia. Biologics. 2013;7:115-22. doi: 10.2147/BTT.S30182. Epub 2013 May 6. [Article]
2. Keller-V Amsberg G, Brummendorf TH: Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia. Expert Rev Anticancer Ther. 2012 Sep;12(9):1121-7. doi: 10.1586/era.12.84. [Article]
3. Drexler HG, MacLeod RA, Uphoff CC: Leukemia cell lines: in vitro models for the study of Philadelphia chromosome-positive leukemia. Leuk Res. 1999 Mar;23(3):207-15. doi: 10.1016/s0145-2126(98)00171-4. [Article]
4. Amsberg GK, Koschmieder S: Profile of bosutinib and its clinical potential in the treatment of chronic myeloid leukemia. Onco Targets Ther. 2013;6:99-106. doi: 10.2147/OTT.S19901. Epub 2013 Mar 4. [Article]
5. Keller G, Schafhausen P, Brummendorf TH: Bosutinib. Recent Results Cancer Res. 2010;184:119-27. doi: 10.1007/978-3-642-01222-8_9. [Article]
6. FDA Approved Drug Products: BOSULIF® (bosutinib) tablets/capsules, for oral use (October 2023) [Link]
7. FDA Approved Drug Products: BOSULIF (bosutinib) tablets, for oral use [Link]
8. Bosutinib Pfizer MSDS [Link]
9. Bosutinib Thermofisher Scientific MSDS [Link]
10. FDA grants accelerated approval to bosutinib for treatment of newly-diagnosed PH+ CML [Link]
11. FDA approves bosutinib for pediatric patients with chronic myelogenous leukemia [Link]

External Links

Human Metabolome Database

HMDB0240205

KEGG Drug

D03252

PubChem Compound

5328940

PubChem Substance

175427079

ChemSpider

4486102

BindingDB

4552

RxNav

1307619

ChEBI

39112

ChEMBL

CHEMBL288441

ZINC

ZINC000022448983

PDBe Ligand

DB8

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Bosutinib

PDB Entries

3soa / 3ue4 / 4mxo / 4mxx / 4mxy / 4mxz / 4qmn / 5ajq / 5i9x / 5vc3 …

show 3 more

FDA label

Download (326 KB)

MSDS

Download (97.1 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Recruiting	Treatment	Chronic Myelogenous Leukemia (CML) / Philadelphia Chromosome Positive (Ph+) Chronic Myeloid Leukemia (CML)	1
4	Terminated	Treatment	Previously Treated PH + CML	1
3	Active Not Recruiting	Treatment	Chronic Myelogenous Leukemia (CML)	1
3	Active Not Recruiting	Treatment	Philadelphia Chromosome Positive (Ph+) Chronic Myeloid Leukemia (CML)	1
3	Completed	Treatment	Chronic Myelogenous Leukemia (CML)	1
3	Completed	Treatment	Leukemia, Myelogenous, Chronic, Breakpoint Cluster Region-Abelson Proto-oncogene (BCR-ABL) Positive	1
2	Active Not Recruiting	Treatment	Chronic Myelogenous Leukemia (CML) / Chronic Myeloid Leukemia in Remission / Philadelphia Chromosome Positive (Ph+) Chronic Myeloid Leukemia (CML)	1
2	Active Not Recruiting	Treatment	Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive	1
2	Completed	Treatment	Autosomal Dominant Polycystic Kidney Disease （ADPKD)	1
2	Completed	Treatment	BCR-ABL Positive / Chronic / Leukemias / Myelogenous	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	100 mg
Tablet	Oral	400 mg
Tablet	Oral	500 mg
Tablet, film coated	Oral	100 mg/1
Tablet, film coated	Oral	100 MG
Tablet, film coated	Oral	400 MG
Tablet, film coated	Oral	400 mg/1
Tablet, film coated	Oral	500 mg/1
Tablet, film coated	Oral	500 MG
Tablet, coated	Oral	500 mg
Tablet, coated	Oral	100 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US6002008	No	1999-12-14	2018-03-27
US7417148	Yes	2008-08-26	2026-06-11
USRE42376	Yes	2011-05-17	2024-10-13
US7767678	Yes	2010-08-03	2027-05-23
US7919625	Yes	2011-04-05	2026-06-11
US11103497	Yes	2021-08-31	2034-08-28

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	131 - 134 °C	Thermofisher MSDS label
logP	3.34	Pfizer MSDS label

Predicted Properties

Property	Value	Source
Water Solubility	0.0095 mg/mL	ALOGPS
logP	4.87	ALOGPS
logP	4.09	Chemaxon
logS	-4.8	ALOGPS
pKa (Strongest Acidic)	15.48	Chemaxon
pKa (Strongest Basic)	8.03	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	8	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	82.88 Å2	Chemaxon
Rotatable Bond Count	9	Chemaxon
Refractivity	142.12 m3·mol-1	Chemaxon
Polarizability	56.02 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9823
Blood Brain Barrier	+	0.9272
Caco-2 permeable	+	0.6542
P-glycoprotein substrate	Substrate	0.7601
P-glycoprotein inhibitor I	Inhibitor	0.8409
P-glycoprotein inhibitor II	Inhibitor	0.9108
Renal organic cation transporter	Inhibitor	0.5663
CYP450 2C9 substrate	Non-substrate	0.854
CYP450 2D6 substrate	Non-substrate	0.6953
CYP450 3A4 substrate	Substrate	0.6987
CYP450 1A2 substrate	Inhibitor	0.5606
CYP450 2C9 inhibitor	Non-inhibitor	0.7372
CYP450 2D6 inhibitor	Non-inhibitor	0.5136
CYP450 2C19 inhibitor	Non-inhibitor	0.5725
CYP450 3A4 inhibitor	Inhibitor	0.5
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.7021
Ames test	AMES toxic	0.5922
Carcinogenicity	Non-carcinogens	0.8869
Biodegradation	Not ready biodegradable	1.0
Rat acute toxicity	2.4201 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Strong inhibitor	0.6147
hERG inhibition (predictor II)	Inhibitor	0.7754

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
MS/MS Spectrum - , positive	LC-MS/MS	splash10-014i-0092000000-68183c460c3cf8e08c01
MS/MS Spectrum - , positive	LC-MS/MS	splash10-001l-1900080000-86f44693fc4098040447

Targets

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Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	0.5	N/A	N/A	A17959
IC 50 (nM)	1.1	N/A	N/A	A27481 / A27749
IC 50 (nM)	20	N/A	N/A	A30641
Kd (nM)	0.029	N/A	N/A	A28058
Kd (nM)	0.036	N/A	N/A	A28058
Kd (nM)	0.037	N/A	N/A	A28058
Kd (nM)	0.039	N/A	N/A	A28058
Kd (nM)	0.047	N/A	N/A	A28058
Kd (nM)	0.057	N/A	N/A	A28058
Kd (nM)	0.062	N/A	N/A	A28058
Kd (nM)	0.086	N/A	N/A	A28058
Kd (nM)	0.11	N/A	N/A	A28058
Kd (nM)	0.12	N/A	N/A	A28058
Kd (nM)	0.18	N/A	N/A	A28058
Kd (nM)	0.63	N/A	N/A	A28058
Kd (nM)	21	N/A	N/A	A28058
Kd (nM)	3.6	N/A	N/A	A28058

Details

Binding Properties1. Tyrosine-protein kinase ABL1

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

Curator comments

Inhibits both endogenous ABL and BCR-ABL fusion protein

General Function

Syntaxin binding

Specific Function

Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility a...

Gene Name

ABL1

Uniprot ID

P00519

Uniprot Name

Tyrosine-protein kinase ABL1

Molecular Weight

122871.435 Da

References

1. FDA Approved Drug Products: BOSULIF® (bosutinib) tablets/capsules, for oral use (October 2023) [Link]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	8	N/A	N/A	A17959
Kd (nM)	4.2	N/A	N/A	A28058

Details

Binding Properties2. Tyrosine-protein kinase Lyn

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Receptor signaling protein tyrosine kinase activity

Specific Function

Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, respons...

Gene Name

LYN

Uniprot ID

P07948

Uniprot Name

Tyrosine-protein kinase Lyn

Molecular Weight

58573.595 Da

References

1. Berndt S, Gurevich VV, Iverson TM: Crystal structure of the SH3 domain of human Lyn non-receptor tyrosine kinase. PLoS One. 2019 Apr 10;14(4):e0215140. doi: 10.1371/journal.pone.0215140. eCollection 2019. [Article]
2. Amsberg GK, Koschmieder S: Profile of bosutinib and its clinical potential in the treatment of chronic myeloid leukemia. Onco Targets Ther. 2013;6:99-106. doi: 10.2147/OTT.S19901. Epub 2013 Mar 4. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	1	N/A	N/A	A17959 / A29600
IC 50 (nM)	1.2	N/A	N/A	A30643 / A30650 / A30651 / A29599
IC 50 (nM)	1.2	7.5	30	A30642 / A30644 / A30648
IC 50 (nM)	1.8	N/A	N/A	A30651
IC 50 (nM)	100	N/A	N/A	A30643 / A30652 / A30653
IC 50 (nM)	3.6	7.5	37	A30646
IC 50 (nM)	3.8	N/A	N/A	A27481 / A30652 / A27749 / A30653
IC 50 (nM)	3.8	7.5	37	A30645 / A30647 / A30649
Kd (nM)	1	N/A	N/A	A28058

Details

Binding Properties3. Proto-oncogene tyrosine-protein kinase Src

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Sh3/sh2 adaptor activity

Specific Function

Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion recept...

Gene Name

SRC

Uniprot ID

P12931

Uniprot Name

Proto-oncogene tyrosine-protein kinase Src

Molecular Weight

59834.295 Da

References

1. FDA Approved Drug Products: BOSULIF® (bosutinib) tablets/capsules, for oral use (October 2023) [Link]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
Kd (nM)	19	N/A	N/A	A28058

Details

Binding Properties4. Dual specificity mitogen-activated protein kinase kinase 1

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Receptor signaling protein tyrosine phosphatase activity

Specific Function

Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones t...

Gene Name

MAP2K1

Uniprot ID

Q02750

Uniprot Name

Dual specificity mitogen-activated protein kinase kinase 1

Molecular Weight

43438.65 Da

References

1. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G: Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
Kd (nM)	9.9	N/A	N/A	A28058

Details

Binding Properties5. Dual specificity mitogen-activated protein kinase kinase 2

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Scaffold protein binding

Specific Function

Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).

Gene Name

MAP2K2

Uniprot ID

P36507

Uniprot Name

Dual specificity mitogen-activated protein kinase kinase 2

Molecular Weight

44423.735 Da

References

1. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G: Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
Kd (nM)	30	N/A	N/A	A28058

Details

Binding Properties6. Mitogen-activated protein kinase kinase kinase 2

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Protein serine/threonine kinase activity

Specific Function

Component of a protein kinase signal transduction cascade. Regulates the JNK and ERK5 pathways by phosphorylating and activating MAP2K5 and MAP2K7 (By similarity). Plays a role in caveolae kiss-and...

Gene Name

MAP3K2

Uniprot ID

Q9Y2U5

Uniprot Name

Mitogen-activated protein kinase kinase kinase 2

Molecular Weight

69740.21 Da

References

1. Ahmad S, Hughes MA, Johnson GL, Scott JE: Development and validation of a high-throughput intrinsic ATPase activity assay for the discovery of MEKK2 inhibitors. J Biomol Screen. 2013 Apr;18(4):388-99. doi: 10.1177/1087057112466430. Epub 2012 Nov 7. [Article]

Binding Properties

×

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	184	N/A	N/A	A17959
Kd (nM)	3600	N/A	N/A	A28058

Details

Binding Properties7. Calcium/calmodulin-dependent protein kinase type II subunit gamma

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Protein homodimerization activity

Specific Function

Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in sarcoplsamic reticulum Ca(2+) transport in skelet...

Gene Name

CAMK2G

Uniprot ID

Q13555

Uniprot Name

Calcium/calmodulin-dependent protein kinase type II subunit gamma

Molecular Weight

62608.655 Da

References

1. Amsberg GK, Koschmieder S: Profile of bosutinib and its clinical potential in the treatment of chronic myeloid leukemia. Onco Targets Ther. 2013;6:99-106. doi: 10.2147/OTT.S19901. Epub 2013 Mar 4. [Article]

Details8. Tyrosine-protein kinase Fgr

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Protein tyrosine kinase activity

Specific Function

Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocy...

Gene Name

FGR

Uniprot ID

P09769

Uniprot Name

Tyrosine-protein kinase Fgr

Molecular Weight

59478.11 Da

References

1. Amsberg GK, Koschmieder S: Profile of bosutinib and its clinical potential in the treatment of chronic myeloid leukemia. Onco Targets Ther. 2013;6:99-106. doi: 10.2147/OTT.S19901. Epub 2013 Mar 4. [Article]

Details9. Tyrosine-protein kinase HCK

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Receptor binding

Specific Function

Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, includ...

Gene Name

HCK

Uniprot ID

P08631

Uniprot Name

Tyrosine-protein kinase HCK

Molecular Weight

59599.355 Da

References

1. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G: Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27. [Article]

Details10. Tyrosine-protein kinase Tec

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Non-receptor tyrosine kinase that contributes to signaling from many receptors and participates as a signal transducer in multiple downstream pathways, including regulation of the actin cytoskeleton. Plays a redundant role to ITK in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. Required for TCR-dependent IL2 gene induction. Phosphorylates DOK1, one CD28-specific substrate, and contributes to CD28-signaling. Mediates signals that negatively regulate IL2RA expression induced by TCR cross-linking. Plays a redundant role to BTK in BCR-signaling for B-cell development and activation, especially by phosphorylating STAP1, a BCR-signaling protein. Required in mast cells for efficient cytokine production. Involved in both growth and differentiation mechanisms of myeloid cells through activation by the granulocyte colony-stimulating factor CSF3, a critical cytokine to promoting the growth, differentiation, and functional activation of myeloid cells. Participates in platelet signaling downstream of integrin activation. Cooperates with JAK2 through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. GRB10, a negative modifier of the FOS activation pathway, is another substrate of TEC. TEC is involved in G protein-coupled receptor- and integrin-mediated signalings in blood platelets. Plays a role in hepatocyte proliferation and liver regeneration and is involved in HGF-induced ERK signaling pathway. TEC regulates also FGF2 unconventional secretion (endoplasmic reticulum (ER)/Golgi-independent mechanism) under various physiological conditions through phosphorylation of FGF2 'Tyr-215'. May also be involved in the regulation of osteoclast differentiation.

Specific Function

Atp binding

Gene Name

TEC

Uniprot ID

P42680

Uniprot Name

Tyrosine-protein kinase Tec

Molecular Weight

73580.73 Da

References

1. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G: Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27. [Article]

Details11. STE20-like serine/threonine-protein kinase

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Protein serine/threonine kinase activity

Specific Function

Mediates apoptosis and actin stress fiber dissolution.

Gene Name

SLK

Uniprot ID

Q9H2G2

Uniprot Name

STE20-like serine/threonine-protein kinase

Molecular Weight

142693.96 Da

References

1. Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G: Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27. [Article]

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Drug created at March 19, 2008 16:41 / Updated at November 24, 2023 04:34