Ибрутиниб

Описание

Ibrutinib (CAS: 936563-96-1) is a first-in-class,potent, orally administered covalently-binding inhibitor of BTK. In November 2013, the US FDA approved ibrutinib (also referred to as PCI-32765), for the treatment of patients with mantle cell lymphoma (MCL) who had received at least one prior therapy. Ibrutinib is a potent inhibitor of BTK that binds covalently to Cys-481 in the active site of BTK, resulting in inhibition of kinase activity. Ibrutinib does have significant activity against 19 other kinases, including seven with a cognate cysteine residue. These include BLK, BMX, ITK, TEC, EGFR, ERBB2, and JAK3.

Использование

Ibrutinib is a highly selective Bruton’s tyrosine kinase (Btk) irreversible inhibitor.

Определение

ChEBI: Ibrutinib is a member of the class of acrylamides that is (3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine in which the piperidine nitrogen is replaced by an acryloyl group. A selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase, it is used for treatment of B-cell malignancies. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a pyrazolopyrimidine, an aromatic amine, an aromatic ether, a member of acrylamides, a N-acylpiperidine and a tertiary carboxamide.

Показания

Ibrutinib is a non-receptor Bruton's tyrosine kinase inhibitor approved for the treatment of relapsed chronic lymphocytic leukemia(CLL), mantle cell lymphoma (MCL) and WaldenstrÖm's Macroglobulinemia (WM).

Общее описание

Class: non-receptor tyrosine kinase
Treatment: CLL, MCL
Oral bioavailability = 4% (fasted), 8% (fed)
Elimination half-life = 3.2 h
Protein binding = 97.3%

Побочные эффекты

The more common side effects of Ibrutinib are diarrhoea and bleeding. Therefore, you should drink plenty of water during treatment, in order to reduce the risk of dehydration using diarrhoea. Bleeding problems can be serious and may even lead to death. This may be manifested by blood or black stools (that look like tar); pink or brown urine; accidental bleeding, or severe or uncontrollable bleeding; spitting up blood or vomit that looks like coffee grounds; coughing up blood; bruising or small red or purple spots on the skin; dizziness; confusing changes in speech; or a headache that lasts for a long time or is severe. Prompt medical attention is needed if a serious condition develops.
Other possible side effects are: increased risk of infection, fever, chills, weakness, confusion, or other signs or symptoms of infection; increased risk of heart disease, rapid and irregular heartbeat; dizziness; lightheadedness; shortness of breath; swelling of the feet, ankles, or legs; discomfort in the chest; or feeling lightheaded. High blood pressure, reduced blood counts, second primary cancer and tumour lysis syndrome (TLS). Different disease treatments exhibit different adverse effects, so the above side effects may not occur in full.

использованная литература

1) Honigberg?et al.?(2010),?The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy;?Proc. Natl. Acad. Sci. USA?107?13075 DOI:10.1073/pnas.1004594107
2) Ponader?et al.?(2012),?The Bruton tyrosine kinase Inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo;?Blood?119?1182
DOI:10.1182/blood-2011-10-386417
3) De Rooij?et al.?(2012),?The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia;?Blood?119?2590
DOI:10.1182/blood-2011-11-390989
4) Pavlasoca?et al.?(2016),?Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis;?Blood?128?1609 DOI:10.1182/blood-2016-04-709519
5) Sagiv-Barfi?et al.?(2015),?Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK; Proc. Natl. Acad. Sci. USA?112?E966 DOI:10.1073/pnas.1500712112
6) Weber?et al.?(2017),?Bruton's Tyrosine Kinase: An Emerging Key Player in Innate Immunity,?Front. Immunol.?8?1454 DOI:10.3389/fimmu.2017.01454