bosutinib   Click here for help

GtoPdb Ligand ID: 5710

Synonyms: Bosulif® | SK 606 | SK-606 | SKI 606
Approved drug PDB Ligand Immunopharmacology Ligand
bosutinib is an approved drug (FDA (2012), EMA (2013))
Compound class: Synthetic organic
Comment: Bosutinib is a Type-1 kinase inhibitor. This compound is a dual inhibitor of Src family kinases and Abl kinase activity [8].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 5
Hydrogen bond donors 1
Rotatable bonds 9
Topological polar surface area 82.88
Molecular weight 529.16
XLogP 3.63
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES COc1cc2c(cc1OCCCN1CCN(CC1)C)ncc(c2Nc1cc(OC)c(cc1Cl)Cl)C#N
Isomeric SMILES COc1cc2c(cc1OCCCN1CCN(CC1)C)ncc(c2Nc1cc(OC)c(cc1Cl)Cl)C#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)
InChI Key UBPYILGKFZZVDX-UHFFFAOYSA-N
No information available.
Summary of Clinical Use Click here for help
Bosutinib is approved for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy. In December 2017, the FDA expanded approval to include treatment of newly-diagnosed chronic phase Ph+ CML [4].
Marketed formulations contain bosutinib monohydrate (PubChem CID 11990828).
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Bosutinib targets the BCR-ABL kinase that promotes CML. In vitro studies have not been able to show bosutinib inhibition of two common imatinib-resistant BCR-ABL mutants, T315I and V299L. Bosutinib is also an inhibitor of some Src-family kinases including Src, Lyn, and Hck.
Pharmacokinetics Click here for help
Absorption/Distribution
Peak concentration is achieved within 4-6 hours of oral administration. 96% of circulating bosutinib is bound to human plasma proteins in healthy subjects. In in vitro studies of transporter associations bosutinib is found to be a substrate and inhibitor of P-glycoprotein.
Biotransformation/Metabolism
Bosutinib is primarily metabolized by CYP3A4, however all of the metabolites are deemed inactive.
Elimination
91% is eliminated in feces and 3% is eliminated in urine.
Population pharmacokinetics
Safety and efficacy of bosutinib have not been established in the pediatric or geriatric populations as appropriate studies have not been performed to demonstrate specific problems that would limit the usefulness of bosutinib in these populations.
Organ function impairment
In patients with pre-existing mild, moderate, and severe hepatic impairment, the daily dose of bosutinib should be reduced to 200 mg, from the 500mg daily dose recommended in patients with normal liver function. With regard to cardiac function, no significant changes in QTc were observed following a single dose of bosutinib.
External links Click here for help
For extended ADME data see the following:

Electronic Medicines Compendium (eMC)
Drugs.com
European Medicines Agency (EMA)