Bosutinib

Bosutinib

Clinical data
Trade names	Bosulif
License data	EU  EMA:  by INN US  DailyMed:  Bosutinib
Routes of administration	By mouth
ATC code	L01EA04 ( WHO )
Legal status
Legal status	AU: S4 (Prescription only) [1] UK: POM (Prescription only) US: ℞-only EU:Rx-only
Pharmacokinetic data
Protein binding	94–96%
Metabolism	By CYP3A4, to inactive metabolites
Elimination half-life	22.5±1.7 hours
Excretion	Fecal (91.3%) and kidney (3%)
Identifiers
IUPAC name 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile
CAS Number	380843-75-4  N
PubChem CID	5328940
IUPHAR/BPS	5710
DrugBank	DB06616  Y
ChemSpider	4486102  Y
UNII	5018V4AEZ0
KEGG	D03252
ChEBI	CHEBI:39112  Y
ChEMBL	ChEMBL288441  Y
CompTox Dashboard (EPA)	DTXSID10861568
ECHA InfoCard	100.149.122
Chemical and physical data
Formula	C26H29Cl2N5O3
Molar mass	530.45 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc1c(OC)cc(c(Cl)c1)Nc4c(C#N)cnc3cc(OCCCN2CCN(CC2)C)c(OC)cc34
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) Y Key:UBPYILGKFZZVDX-UHFFFAOYSA-N Y
NY  (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

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

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

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

Interactions

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.

See also

• Discovery and development of Bcr-Abl tyrosine kinase inhibitors

References

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. "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. PMID   31643176. 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.