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.

Notes

See also

Discovery and development of Bcr-Abl tyrosine kinase inhibitors

References

^ "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.
^ 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.
^ ^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.
^ 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.
^ Bosutinib. 2012. Archived from the original on 3 April 2018. Retrieved 2 April 2018. {{cite book}}: |website= ignored (help)
^ 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.
^ 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.
^ "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.
^ "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.
^ "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.
^ "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.

External links

"Bosutinib". Drug Information Portal. U.S. National Library of Medicine.

Targeted cancer therapy / antineoplastic agents (L01)

CI monoclonal antibodies ("-mab")

Receptor tyrosine kinase	ErbB: HER1/EGFR (Cetuximab Panitumumab) HER2/neu (Pertuzumab Trastuzumab (+hyaluronidase) Trastuzumab emtansine Trastuzumab deruxtecan Zanidatamab )
Others for solid tumors	EpCAM (Catumaxomab Edrecolomab) VEGF-A (Bevacizumab)
Leukemia/lymphoma	lymphoid: CD3 (Glofitamab, Elranatamab, Mosunetuzumab), CD20 (Glofitamab Ibritumomab Mosunetuzumab Obinutuzumab Ofatumumab Rituximab Tositumomab), CD30 (Brentuximab), CD52 (Alemtuzumab) myeloid: CD33 (Gemtuzumab ozogamicin)
Other	Amivantamab Atezolizumab (+hyaluronidase) Avelumab Axatilimab Belantamab mafodotin Bermekimab Blinatumomab Cemiplimab Daratumumab Dinutuximab beta Dostarlimab Durvalumab Elotuzumab Enfortumab vedotin Epcoritamab Inotuzumab ozogamicin Ipilimumab Isatuximab Loncastuximab tesirine Mirvetuximab soravtansine Mogamulizumab Moxetumomab pasudotox Naxitamab Necitumumab Nivolumab Olaratumab Oportuzumab monatox Pembrolizumab Polatuzumab vedotin Prolgolimab Ramucirumab Retifanlimab Sabatolimab Sacituzumab govitecan Serplulimab Sugemalimab Tafasitamab Talquetamab Tarlatamab Teclistamab Tislelizumab Tisotumab vedotin Toripalimab Tremelimumab Zolbetuximab

Tyrosine kinase inhibitors ("-nib")

Receptor tyrosine kinase

HER1/EGFR and HER2/neu

BRAF

RTK class III: C-kit and PDGFR (Avapritinib
Axitinib
Masitinib
Pazopanib
Ripretinib
Sorafenib
Sunitinib
Toceranib)
FLT3 (Lestaurtinib, Gilteritinib (AXL, ALK, LTK))

VEGFR
- Axitinib
- Cediranib
- Fruquintinib
- Lenvatinib
- Nintedanib
- Pazopanib
- Regorafenib
- Semaxanib
- Sorafenib
- Sunitinib
- Tivozanib
- Toceranib
- Vandetanib

ALK

RET inhibitors: Entrectinib (ALK, ROS1, NTRK), Futibatinib (FGFR2), Infigratinib, Larotrectinib (NTRK), Pemigatinib (FGFR), Pralsetinib, Repotrectinib (ROS1, TRK, ALK), Selpercatinib (VEGFR, FGFR), Vandetanib (VEGFR, EGFR).

c-MET inhibitors: Cabozantinib (VEGFR), Capmatinib, Crizotinib (ALK)

bcr-abl
- Asciminib
- Bosutinib
- Dasatinib
- Imatinib
- Nilotinib
- Ponatinib
- Radotinib

Src (Bosutinib
Dasatinib)

Janus kinase (JAK)

MAP2K (MEK)

EML4-ALK

Bruton's (BTK)

Other

fusion protein against VEGF (Aflibercept)

proapoptotic peptide against ANXA2 and prohibitin (Adipotide)

exotoxin against IL-2 (Denileukin diftitox)

mTOR inhibitors

hedgehog inhibitors

CDK inhibitors

KRAS inhibitors
- Adagrasib
- Sotorasib

Pi3K inhibitors

Menin inhibitors
- Revumenib

Fibroblast growth factor receptor (FGFR) inhibitors
Erdafitinib
Futibatinib
Infigratinib
Pemigatinib

Growth factor receptor modulators

Agonists: Angiopoietin 1
Angiopoietin 4

Antagonists: Angiopoietin 2
Angiopoietin 3

Kinase inhibitors: Altiratinib
CE-245677
Rebastinib

Antibodies: Evinacumab (against angiopoietin 3)
Nesvacumab (against angiopoietin 2)

Agonists: Axokine
CNTF
Dapiclermin

EGF (ErbB1/HER1)	Agonists: Amphiregulin Betacellulin EGF (urogastrone) Epigen Epiregulin Heparin-binding EGF-like growth factor (HB-EGF) Murodermin Nepidermin Transforming growth factor alpha (TGFα) Kinase inhibitors: Afatinib Agerafenib Brigatinib Canertinib Dacomitinib Erlotinib Gefitinib Grandinin Icotinib Lapatinib Neratinib Osimertinib Vandetanib WHI-P 154 Antibodies: Cetuximab Depatuxizumab Depatuxizumab mafodotin Futuximab Imgatuzumab Matuzumab Necitumumab Nimotuzumab Panitumumab Zalutumumab
ErbB2/HER2	Agonists: Unknown/none Antibodies: Ertumaxomab Pertuzumab Trastuzumab Trastuzumab deruxtecan Trastuzumab duocarmazine Trastuzumab emtansine Kinase inhibitors: Afatinib Lapatinib Mubritinib Neratinib Tucatinib
ErbB3/HER3	Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C)) Antibodies: Duligotumab Patritumab Seribantumab
ErbB4/HER4	Agonists: Betacellulin Epigen Heparin-binding EGF-like growth factor (HB-EGF) Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))

FGFR1	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20) Repifermin Selpercatinib Trafermin Velafermin
FGFR2	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22) Palifermin Repifermin Selpercatinib Sprifermin Trafermin Antibodies: Aprutumab Aprutumab ixadotin Kinase inhibitors: Infigratinib
FGFR3	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 8, 9, 18, 23) Selpercatinib Sprifermin Trafermin Antibodies: Burosumab (against FGF23)
FGFR4	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 6, 8, 9, 19) Trafermin
Unsorted	Agonists: FGF15/19

Agonists: Fosgonimeton
Hepatocyte growth factor

Potentiators: Dihexa (PNB-0408)

IGF-1	Agonists: des(1-3)IGF-1 Insulin-like growth factor-1 (somatomedin C) IGF-1 LR3 Insulin-like growth factor-2 (somatomedin A) Insulin Mecasermin Mecasermin rinfabate Kinase inhibitors: BMS-754807 Linsitinib NVP-ADW742 NVP-AEW541 OSl-906 Antibodies: AVE-1642 Cixutumumab Dalotuzumab Figitumumab Ganitumab Robatumumab R1507 Teprotumumab Xentuzumab (against IGF-1 and IGF-2)
IGF-2	Agonists: Insulin-like growth factor-2 (somatomedin A) Antibodies: Dusigitumab Xentuzumab (against IGF-1 and IGF-2)
Others	Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7) Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1) Trofinetide

Antibodies: Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab

Aptamers: Against NGF: RBM-004

Decoy receptors: LEVI-04 (p75^NTR-Fc)

Agonists: Becaplermin
Platelet-derived growth factor (A, B, C, D)

GFRα1	Agonists: Glial cell line-derived neurotrophic factor (GDNF) Liatermin Kinase inhibitors: Vandetanib
GFRα2	Agonists: Neurturin (NRTN) Kinase inhibitors: Vandetanib
GFRα3	Agonists: Artemin (ARTN) Kinase inhibitors: Vandetanib
GFRα4	Agonists: Persephin (PSPN) Kinase inhibitors: Vandetanib
Unsorted	Kinase inhibitors: Agerafenib

Agonists: Ancestim
Stem cell factor

See here instead.

TrkA	Agonists: Amitriptyline BNN-20 BNN-27 Cenegermin DHEA DHEA-S Gambogic amide NGF Tavilermide Antagonists: ALE-0540 Dexamethasone FX007 Testosterone Negative allosteric modulators: VM-902A Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib Milciclib ONO-4474 ONO-5390556 PLX-7486 Rebastinib SNA-120 (pegylated K252a)) Antibodies: Against TrkA: GBR-900; Against NGF: ABT-110 (PG110) ASP-6294 Fasinumab Frunevetmab Fulranumab MEDI-578 Ranevetmab Tanezumab Aptamers: Against NGF: RBM-004 Decoy receptors: ReN-1820 (TrkAd5)
TrkB	Agonists: 3,7-DHF 3,7,8,2'-THF 4'-DMA-7,8-DHF 7,3'-DHF 7,8-DHF 7,8,2'-THF 7,8,3'-THF Amitriptyline BDNF BNN-20 Deoxygedunin Deprenyl Diosmetin DMAQ-B1 HIOC LM22A-4 N-Acetylserotonin NT-3 NT-4 Norwogonin (5,7,8-THF) R7 R13 TDP6 Antagonists: ANA-12 Cyclotraxin B Gossypetin (3,5,7,8,3',4'-HHF) Ligands: DHEA Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib ONO-4474 ONO-5390556 PLX-7486
TrkC	Agonists: BNN-20 DHEA NT-3 Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib ONO-4474 ONO-5390556 PLX-7486

Agonists: Placental growth factor (PGF)
Ripretinib
Telbermin
VEGF (A, B, C, D (FIGF))

Allosteric modulators: Cyclotraxin B

Decoy receptors: Aflibercept

Others

Additional growth factors: Adrenomedullin
Colony-stimulating factors (see here instead)
Connective tissue growth factor (CTGF)
Ephrins (A1, A2, A3, A4, A5, B1, B2, B3)
Erythropoietin (see here instead)
Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)
Glia maturation factor (GMF)
Hepatoma-derived growth factor (HDGF)
Interleukins/T-cell growth factors (see here instead)
Leukemia inhibitory factor (LIF)
Macrophage-stimulating protein (MSP; HLP, HGFLP)
Midkine (NEGF2)
Migration-stimulating factor (MSF; PRG4)
Oncomodulin
Pituitary adenylate cyclase-activating peptide (PACAP)
Pleiotrophin
Renalase
Thrombopoietin (see here instead)
Wnt signaling proteins

Additional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)

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This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed.Find sources: The Heaven Sword and Dragon Saber 2000 TV series – news · newspapers · books · scholar · JSTOR (February 2010) (Learn how and when to remove this message) Hong Kong TV series or program The Heaven Sword and Dragon SaberTVB posterAlso known asThe Heaven Swo...

UFC on Fox: Lawler vs. dos Anjos

UFC_on_Fox:_Lawler_vs._dos_Anjos

UFC on Fox: Lawler vs. Don AnjosProdotto daUltimate Fighting Championship Data16 dicembre 2017 Città Winnipeg, Canada SedeBell MTS Place Spettatori8 862[1] Cronologia pay-per-viewUFC Fight Night: Swanson vs. OrtegaUFC on Fox: Lawler vs. Don AnjosUFC 219: Cyborg vs. Holm Progetto Wrestling Manuale UFC on Fox: Lawler vs. Don Anjos (conosciuto anche come UFC on Fox 26) è stato un evento di arti marziali miste tenuto dalla Ultimate Fighting Championship il 16 dicembre 2017 al Bell ...

エレクトロニック・アレイズ

エレクトロニック・アレイズElectronic Arrays, Inc. 以前の社名マクマレン・アソシエイツ(1967年まで)業種電卓用半導体開発その後 NEC設立アメリカ合衆国創業者ジョン・マクマレン解散 1978年製品電卓用半導体エレクトロニック・アレイズ（Electronic Arrays, Inc.）は、1960年代から70年代にかけて存在した米国の集積回路（IC）製造会社である。沿革ジョン・マクマレンらゼ�...

Mahalanobis distance

Mahalanobis_distance

Statistical distance measure The Mahalanobis distance is a measure of the distance between a point P {\displaystyle P} and a distribution D {\displaystyle D} , introduced by P. C. Mahalanobis in 1936.[1] The mathematical details of Mahalanobis distance has appeared in the Journal of The Asiatic Society of Bengal.[2] Mahalanobis's definition was prompted by the problem of identifying the similarities of skulls based on measurements (the earliest work related to similaritie...