Bosutinib
{{Short description|Chemical compound}}
{{Use dmy dates|date=November 2021}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477373749
| IUPAC_name = 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile
| image = Bosutinib.svg
| width = 270
| image2 = Bosutinib3Dan2.gif
| width2 = 240
| tradename = Bosulif
| licence_EU = yes
| DailyMedID = Bosutinib
| pregnancy_AU =
| pregnancy_category =
| routes_of_administration = By mouth
| ATC_prefix = L01
| ATC_suffix = EA04
| ATC_supplemental =
| legal_AU = S4
| legal_CA =
| legal_UK = POM
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_status =
| bioavailability =
| protein_bound = 94–96%
| metabolism = By CYP3A4, to inactive metabolites
| elimination_half-life = 22.5±1.7 hours
| excretion = Fecal (91.3%) and kidney (3%)
| IUPHAR_ligand = 5710
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 380843-75-4
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 39112
| PubChem = 5328940
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06616
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 5018V4AEZ0
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 288441
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4486102
| KEGG = D03252
| smiles = Clc1c(OC)cc(c(Cl)c1)Nc4c(C#N)cnc3cc(OCCCN2CCN(CC2)C)c(OC)cc34
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = UBPYILGKFZZVDX-UHFFFAOYSA-N
| C=26 | H=29 | Cl=2 | N=5 | O=3
}}
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.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.
Originally synthesized by Wyeth, it is being developed by Pfizer.{{cn|date=April 2023}}
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).{{cite journal | vauthors = Daud AI, Krishnamurthi SS, Saleh MN, Gitlitz BJ, Borad MJ, Gold PJ, Chiorean EG, Springett GM, Abbas R, Agarwal S, Bardy-Bouxin N, Hsyu PH, Leip E, Turnbull K, Zacharchuk C, Messersmith WA | display-authors = 6 | title = Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors | journal = Clinical Cancer Research | volume = 18 | issue = 4 | pages = 1092–100 | date = February 2012 | pmid = 22179664 | doi = 10.1158/1078-0432.CCR-11-2378 | doi-access = free | url = https://aacr.figshare.com/articles/journal_contribution/Supplementary_Figure_1_from_Phase_I_Study_of_Bosutinib_a_Src_Abl_Tyrosine_Kinase_Inhibitor_Administered_to_Patients_with_Advanced_Solid_Tumors/22444170/1/files/39895179.pdf }} It has also shown activity against the receptors for platelet derived growth factor and vascular endothelial growth factor.{{cite book|title=Bosutinib|url=https://livertox.nih.gov/Bosutinib.htm|website=livertox.nih.gov|year=2012|access-date=2 April 2018|archive-date=3 April 2018|archive-url=https://web.archive.org/web/20180403051548/https://livertox.nih.gov/Bosutinib.htm|url-status=live}} 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.
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.{{cite journal | vauthors = Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C | display-authors = 6 | title = Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib | journal = Blood | volume = 118 | issue = 17 | pages = 4567–76 | date = October 2011 | pmid = 21865346 | pmc = 4916618 | doi = 10.1182/blood-2011-05-355594 }}{{cite journal | vauthors = Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C | display-authors = 6 | title = Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial | journal = Journal of Clinical Oncology | volume = 30 | issue = 28 | pages = 3486–92 | date = October 2012 | pmid = 22949154 | pmc = 4979199 | doi = 10.1200/JCO.2011.38.7522 }}{{cite news |url=http://www.empr.com/bosulif-approved-for-previously-treated-philadelphia-chromosome-positive-chronic-myelogenous-leukemia/article/257548/ |title=Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia |date=5 September 2012 |access-date=6 September 2012 |archive-date=24 September 2015 |archive-url=https://web.archive.org/web/20150924000237/http://www.empr.com/bosulif-approved-for-previously-treated-philadelphia-chromosome-positive-chronic-myelogenous-leukemia/article/257548/ |url-status=live }}{{cite web|title=Bosulif : EPAR - Product Information|work=European Medicines Agency|publisher=Pfitzer Ltd|date=9 April 2013|access-date=3 January 2014|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002373/WC500141721.pdf|archive-date=3 January 2014|archive-url=https://web.archive.org/web/20140103142404/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002373/WC500141721.pdf|url-status=live}}
Contraindications
Bosutinib has two known absolute contraindications, which are: known hypersensitivity to bosutinib and liver impairment.{{cite web|title=Bosulif 100mg and 500mg Tablets - Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Pfitzer Limited|date=7 June 2013|access-date=3 January 2014|url=http://www.medicines.org.uk/emc/medicine/27795/SPC/Bosulif+100mg+and+500mg+Tablets/|archive-date=3 January 2014|archive-url=https://web.archive.org/web/20140103182530/http://www.medicines.org.uk/emc/medicine/27795/SPC/Bosulif+100mg+and+500mg+Tablets/|url-status=live}}{{cite web|title=BOSULIF (bosutinib monohydrate) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]|work=DailyMed|publisher=Pfitzer Inc|date=September 2013|access-date=3 January 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=adc84ad5-a04d-4fee-9ba8-91f7abd928e3|archive-date=3 January 2014|archive-url=https://web.archive.org/web/20140103190716/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=adc84ad5-a04d-4fee-9ba8-91f7abd928e3|url-status=live}}
Interactions
Bosutinib is both a substrate and an inhibitor of P-glycoprotein (P-gp) and CYP3A4. Hence P-gp and CYP3A4 inhibitors may increase plasma levels of bosutinib.{{cite web|title=Bosulif (bosutinib) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=3 January 2014|url=http://reference.medscape.com/drug/bosulif-bosutinib-999770#showall|archive-date=3 January 2014|archive-url=https://web.archive.org/web/20140103192948/http://reference.medscape.com/drug/bosulif-bosutinib-999770#showall|url-status=live}} Likewise CYP3A4 inducers may reduce plasma concentrations of bosutinib. 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.
File:WEE1 KINASE DOMAIN IN COMPLEX WITH BOSUTINIB.png kinase domain in complex with bosutinib.]]
Notes
{{reflist|group = Note}}
See also
References
{{Reflist}}
External links
- {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/bosutinib | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Bosutinib }}
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Category:Non-receptor tyrosine kinase inhibitors