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
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
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAccelerated phase chronic myelogenous leukemia (cml)••••••••••••••••••••••••••• •• ••••••••••• •• ••••• ••••••••••••••• ••••••
Treatment ofChronic phase chronic myeloid leukemia•••••••••••••••••• •••••••••••••• ••••••••••••••••• ••••••
Treatment ofChronic phase chronic myeloid leukemia•••••••••••••••••• ••••••••••••••••••• •• ••••••••••• •• ••••• ••••••••••••••• ••••••
Treatment ofBlast phase chronic myelocytic 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

TargetActionsOrganism
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 Cmax 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 Cmax was 127 ng/mL (31%), Ctrough was 68 ng/mL (39%) and AUC was 2370 ng•h/mL (34%) following multiple oral doses of bosutinib 400 mg. Bosutinib steady-state Cmax was 171 ng/mL (38%), Ctrough 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) tmax 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 Cmax 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 Cmax 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.

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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 (t1/2) 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
PathwayCategory
Bosutinib Inhibition of BCR-ABLDrug 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.
DrugInteraction
AbametapirThe serum concentration of Bosutinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Bosutinib can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Bosutinib.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Bosutinib.
AbrocitinibThe serum concentration of Bosutinib can be increased when it is combined with Abrocitinib.
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.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Bosutinib monohydrate844ZJE6I55918639-08-4BXPOSPOKHGNMEP-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BosulifTablet, film coated500 mgOralPfizer Europe Ma Eeig2016-09-08Not applicableEU flag
BosulifCapsule100 mg/1OralPfizer Laboratories Div Pfizer Inc2024-01-02Not applicableUS flag
BosulifTablet400 mgOralPfizer Canada UlcNot applicableNot applicableCanada flag
BosulifTablet, film coated400 mg/1OralPfizer Laboratories Div Pfizer Inc2017-12-18Not applicableUS flag
BosulifTablet, film coated100 mgOralPfizer Europe Ma Eeig2016-09-08Not applicableEU flag

Categories

ATC Codes
L01EA04 — Bosutinib
Drug Categories
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
show 8 more
Substituents
1,3-dichlorobenzene / 1,4-diazinane / 4-aminoquinoline / Alkyl aryl ether / Amine / Aminophenyl ether / Aminopyridine / Aniline or substituted anilines / Anisole / Aromatic heteropolycyclic compound
show 30 more
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]
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

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral100 mg/1
CapsuleOral50 mg/1
TabletOral100 mg
TabletOral400 mg
TabletOral500 mg
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral100 MG
Tablet, film coatedOral400 MG
Tablet, film coatedOral400 mg/1
Tablet, film coatedOral500 MG
Tablet, film coatedOral500 mg/1
Tablet, coatedOral50000000 mg
Tablet, coatedOral100 mg
Tablet, coatedOral500 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6002008No1999-12-142018-03-27US flag
US7417148Yes2008-08-262026-06-11US flag
USRE42376Yes2011-05-172024-10-13US flag
US7767678Yes2010-08-032027-05-23US flag
US7919625Yes2011-04-052026-06-11US flag
US11103497Yes2021-08-312034-08-28US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)131 - 134 °CThermofisher MSDS label
logP3.34Pfizer MSDS label
Predicted Properties
PropertyValueSource
Water Solubility0.0095 mg/mLALOGPS
logP4.87ALOGPS
logP4.09Chemaxon
logS-4.8ALOGPS
pKa (Strongest Acidic)15.48Chemaxon
pKa (Strongest Basic)8.03Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area82.88 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity142.12 m3·mol-1Chemaxon
Polarizability56.02 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9823
Blood Brain Barrier+0.9272
Caco-2 permeable+0.6542
P-glycoprotein substrateSubstrate0.7601
P-glycoprotein inhibitor IInhibitor0.8409
P-glycoprotein inhibitor IIInhibitor0.9108
Renal organic cation transporterInhibitor0.5663
CYP450 2C9 substrateNon-substrate0.854
CYP450 2D6 substrateNon-substrate0.6953
CYP450 3A4 substrateSubstrate0.6987
CYP450 1A2 substrateInhibitor0.5606
CYP450 2C9 inhibitorNon-inhibitor0.7372
CYP450 2D6 inhibitorNon-inhibitor0.5136
CYP450 2C19 inhibitorNon-inhibitor0.5725
CYP450 3A4 inhibitorInhibitor0.5
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7021
Ames testAMES toxic0.5922
CarcinogenicityNon-carcinogens0.8869
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.4201 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.6147
hERG inhibition (predictor II)Inhibitor0.7754
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
MS/MS Spectrum - , positiveLC-MS/MSsplash10-014i-0092000000-68183c460c3cf8e08c01
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001l-1900080000-86f44693fc4098040447
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0000090000-857b31ff0ea2cc297089
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0000090000-c18a55afd1ed4c748f0e
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0500970000-f02e39ff1eec16e7947b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0104690000-afb6203f70a8b4fa10cd
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0903340000-75eed11cb3828e12536d
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0089-3307920000-29d2249d4ff2d576e643
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-235.5973979
predicted
DarkChem Lite v0.1.0
[M-H]-213.89542
predicted
DeepCCS 1.0 (2019)
[M+H]+236.7142979
predicted
DarkChem Lite v0.1.0
[M+H]+216.25343
predicted
DeepCCS 1.0 (2019)
[M+Na]+236.8075979
predicted
DarkChem Lite v0.1.0
[M+Na]+223.04863
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Filppula AM, Neuvonen PJ, Backman JT: In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9. doi: 10.1124/dmd.114.057695. Epub 2014 Apr 8. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Filppula AM, Neuvonen PJ, Backman JT: In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9. doi: 10.1124/dmd.114.057695. Epub 2014 Apr 8. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Skoglund K, Moreno SB, Baytar M, Jonsson JI, Green H: ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro. Pharmgenomics Pers Med. 2013 Aug 20;6:63-72. doi: 10.2147/PGPM.S45522. eCollection 2013. [Article]

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