Bosutinib (

rINN Rinn is a municipality in the district of Innsbruck-Land in the Austrian state of Tyrol located 6 km southeast of Innsbruck. The village was mentioned in documents as “Runne” in 1250 for the first time. Population Climate Climate typ ...

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...

; codenamed SKI-606, marketed under the trade name Bosulif) is a small molecule

BCR-ABL The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

and src

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

used for the treatment of chronic myelogenous leukemia. Originally synthesized by

Wyeth Wyeth, LLC was an American pharmaceutical company. The company was founded in Philadelphia, Pennsylvania, in 1860 as ''John Wyeth and Brother''. It was later known, in the early 1930s, as American Home Products, before being renamed to Wyeth in ...

, it is being developed by

Pfizer Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...

Mechanism

It is an ATP-competitive

Bcr-Abl tyrosine-kinase inhibitor Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadel ...

with an additional inhibitory effect on

Src family kinases Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs i ...

(including Src, Lyn and Hck). It has also shown activity against the receptors for

platelet derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing bloo ...

and

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

. 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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

and EU European Medicines Agency approval in September 2012, and March 2013, respectively for the treatment of adults with

Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.

Contraindications

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

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. 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. WEE1 KINASE DOMAIN IN COMPLEX WITH BOSUTINIB

WEE1 KINASE DOMAIN IN COMPLEX WITH BOSUTINIB

Notes

References

External links

* {{Portal bar , Medicine Non-receptor tyrosine kinase inhibitors Piperazines Catechol ethers Quinolines Aromatic nitriles Anilines Chloroarenes Pfizer brands