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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2D Structure
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Physico-chemical Properties
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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
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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)
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
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.
Bosutinib is primarily metabolized by CYP3A4, however all of the metabolites are deemed inactive.
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.
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