{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{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 = Bosutinib2DACS.svg | image_class = skin-invert-image | width = 270 | image2 = Bosutinib3Dan2.gif | image_class2 = bg-transparent | width2 = 240 <!--Clinical data-->| tradename = Bosulif | licence_EU = yes | DailyMedID = Bosutinib | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_category = | routes_of_administration = By mouth | ATC_prefix = L01 | ATC_suffix = EA04 | ATC_supplemental = | legal_AU = S4 | legal_AU_comment = <ref>{{cite web | title = Prescription medicines: registration of new chemical entities in Australia, 2014 | date = 21 June 2022 | website = Therapeutic Goods Administration (TGA) | url = https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | access-date = 10 April 2023 | archive-date = 10 April 2023 | archive-url = https://web.archive.org/web/20230410065838/https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 | url-status = live }}</ref> | legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_UK = POM | legal_US = Rx-only | legal_EU = Rx-only | legal_status = <!--Pharmacokinetic data--> | 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%)
<!--Identifiers-->| 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
<!--Chemical data-->| 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.<ref>{{cite journal | vauthors = Lipton JH, Brümmendorf TH, Sweet K, Apperley JF, Cortes JE | title = Practical considerations in the management of patients treated with bosutinib for chronic myeloid leukemia | journal = Annals of Hematology | volume = 103 | issue = 9 | pages = 3429–3442 | date = September 2024 | pmid = 39023573 | pmc = 11358173 | doi = 10.1007/s00277-024-05851-4 }}</ref>
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).<ref name="MSR" /><ref>{{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 | 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 = 1092–1100 | date = February 2012 | pmid = 22179664 | doi = 10.1158/1078-0432.CCR-11-2378 | doi-access = free }}</ref> It has also shown activity against the receptors for platelet derived growth factor and vascular endothelial growth factor.<ref>{{cite book | chapter = Bosutinib | title = LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet] | location = Bethesda (MD) | publisher = National Institute of Diabetes and Digestive and Kidney Diseases | year = 2012 | pmid = 31643176 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK547951/ }}</ref> 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.<ref name="MSR" />
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.<ref>{{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 | 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 = 4567–4576 | date = October 2011 | pmid = 21865346 | pmc = 4916618 | doi = 10.1182/blood-2011-05-355594 }}</ref><ref>{{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 | 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 = 3486–3492 | date = October 2012 | pmid = 22949154 | pmc = 4979199 | doi = 10.1200/JCO.2011.38.7522 }}</ref><ref>{{cite news | title = Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia | date = 5 September 2012 | url = http://www.empr.com/bosulif-approved-for-previously-treated-philadelphia-chromosome-positive-chronic-myelogenous-leukemia/article/257548/ | 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 | via = Medical Professionals Reference (MPR) }}</ref><ref>{{cite web | title = Bosulif : EPAR - Product Information | date = 9 April 2013 | work = European Medicines Agency | publisher = Pfizer Ltd | 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 }}</ref>
== Contraindications==
Bosutinib has two known absolute contraindications, which are: known hypersensitivity to bosutinib and liver impairment.<ref name="EMC">{{cite web | title = Bosulif 100mg and 500mg Tablets - Summary of Product Characteristics (SPC) | date = 7 June 2013 | work = electronic Medicines Compendium | publisher = Pfitzer Limited | 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 }}</ref><ref name="DM">{{cite web | title = BOSULIF (bosutinib monohydrate) tablet, film coated [Pfizer Laboratories Div Pfizer Inc] | date = September 2013 | work = DailyMed | publisher = Pfitzer Inc | access-date = 3 January 2014 | url = https://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 }}</ref>
== Interactions ==
Bosutinib is both a substrate and an inhibitor of P-glycoprotein (P-gp) and CYP3A4.<ref name="MSR" /> Hence P-gp and CYP3A4 inhibitors may increase plasma levels of bosutinib.<ref name = MSR>{{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 }}</ref> Likewise CYP3A4 inducers may reduce plasma concentrations of bosutinib.<ref name="MSR" /> 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.<ref name="MSR" />
[[File:WEE1 KINASE DOMAIN IN COMPLEX WITH BOSUTINIB.png|thumb|300px|class=skin-invert-image|WEE1 kinase domain in complex with bosutinib.]]
==Notes== {{reflist|group = Note}}
== See also == *Discovery and development of Bcr-Abl tyrosine kinase inhibitors
== References == {{Reflist}}
{{Targeted cancer therapeutic agents}} {{Growth factor receptor modulators}} {{Portal bar | Medicine}}
Category:Non-receptor tyrosine kinase inhibitors Category:4-Methylpiperazin-1-yl compounds Category:Catechol ethers Category:Quinolines Category:Cyanopyridines Category:Anilines Category:Chloroarenes Category:Drugs developed by Pfizer