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Bosutinib

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Bosutinib
Clinical data
Trade namesBosulif
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)[1]
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
Protein binding94–96%
MetabolismBy CYP3A4, to inactive metabolites
Elimination half-life22.5±1.7 hours
ExcretionFecal (91.3%) and kidney (3%)
Identifiers
  • 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.149.122 Edit this at Wikidata
Chemical and physical data
FormulaC26H29Cl2N5O3
Molar mass530.45 g·mol−1
3D model (JSmol)
  • Clc1c(OC)cc(c(Cl)c1)Nc4c(C#N)cnc3cc(OCCCN2CCN(CC2)C)c(OC)cc34
  • 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) checkY
  • Key:UBPYILGKFZZVDX-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Bosutinib, sold under the brand name Bosulif, is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.[2]

Originally synthesized by Wyeth, it is being developed by Pfizer.[citation needed]

Mechanism

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It is an ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an additional inhibitory effect on Src family kinases (including Src, Lyn and Hck).[3][4] It has also shown activity against the receptors for platelet derived growth factor and vascular endothelial growth factor.[5] Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, but did not inhibit T315I and V299L mutant cells.[3]

Bosutinib is metabolized through CYP3A4.

Medical uses

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Bosutinib received US FDA and EU European Medicines Agency approval in September 2012, and March 2013, respectively for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.[6][7][8][9]

Contraindications

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Bosutinib has two known absolute contraindications, which are: known hypersensitivity to bosutinib and liver impairment.[10][11]

Interactions

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Bosutinib is both a substrate and an inhibitor of P-glycoprotein (P-gp) and CYP3A4.[3] Hence P-gp and CYP3A4 inhibitors may increase plasma levels of bosutinib.[3] Likewise CYP3A4 inducers may reduce plasma concentrations of bosutinib.[3] It may also alter the metabolism and uptake (into the GIT by means of its P-gp inhibitory effects) of other drugs that are substrates for P-gp and CYP3A4.[3]

WEE1 kinase domain in complex with bosutinib.

Notes

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See also

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References

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  1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  2. ^ Lipton JH, Brümmendorf TH, Sweet K, Apperley JF, Cortes JE. Practical considerations in the management of patients treated with bosutinib for chronic myeloid leukemia. Ann Hematol. 2024 Jul 18. doi: 10.1007/s00277-024-05851-4. Epub ahead of print. PMID: 39023573.
  3. ^ a b c d e f "Bosulif (bosutinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 3 January 2014. Retrieved 3 January 2014.
  4. ^ Daud AI, Krishnamurthi SS, Saleh MN, Gitlitz BJ, Borad MJ, Gold PJ, et al. (February 2012). "Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors" (PDF). Clinical Cancer Research. 18 (4): 1092–100. doi:10.1158/1078-0432.CCR-11-2378. PMID 22179664.
  5. ^ Bosutinib. 2012. Archived from the original on 3 April 2018. Retrieved 2 April 2018. {{cite book}}: |website= ignored (help)
  6. ^ Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, et al. (October 2011). "Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib". Blood. 118 (17): 4567–76. doi:10.1182/blood-2011-05-355594. PMC 4916618. PMID 21865346.
  7. ^ Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, et al. (October 2012). "Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial". Journal of Clinical Oncology. 30 (28): 3486–92. doi:10.1200/JCO.2011.38.7522. PMC 4979199. PMID 22949154.
  8. ^ "Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia". 5 September 2012. Archived from the original on 24 September 2015. Retrieved 6 September 2012.
  9. ^ "Bosulif : EPAR - Product Information" (PDF). European Medicines Agency. Pfitzer Ltd. 9 April 2013. Archived (PDF) from the original on 3 January 2014. Retrieved 3 January 2014.
  10. ^ "Bosulif 100mg and 500mg Tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfitzer Limited. 7 June 2013. Archived from the original on 3 January 2014. Retrieved 3 January 2014.
  11. ^ "BOSULIF (bosutinib monohydrate) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]". DailyMed. Pfitzer Inc. September 2013. Archived from the original on 3 January 2014. Retrieved 3 January 2014.
[edit]
  • "Bosutinib". Drug Information Portal. U.S. National Library of Medicine.
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