Ibrutinib

From Wikipedia, the free encyclopedia - View original article

Ibrutinib
Ibrutinib.svg
Systematic (IUPAC) name
1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
Clinical data
Trade namesImbruvica
Licence dataUS FDA:link
Pregnancy cat.D (US)
Legal status-only (US)
Pharmacokinetic data
Protein binding97.3%
MetabolismHepatic (CYP3A & CYP2D6)
Half-life4-6 hours
ExcretionFaeces (80%), urine (10%)
Identifiers
CAS number936563-96-1
ATC code?
PubChemCID 24821094
ChemSpider26637187
ChEBICHEBI:76612
Chemical data
FormulaC25H24N6O2 
Mol. mass440.4971
 
Jump to: navigation, search
Ibrutinib
Ibrutinib.svg
Systematic (IUPAC) name
1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
Clinical data
Trade namesImbruvica
Licence dataUS FDA:link
Pregnancy cat.D (US)
Legal status-only (US)
Pharmacokinetic data
Protein binding97.3%
MetabolismHepatic (CYP3A & CYP2D6)
Half-life4-6 hours
ExcretionFaeces (80%), urine (10%)
Identifiers
CAS number936563-96-1
ATC code?
PubChemCID 24821094
ChemSpider26637187
ChEBICHEBI:76612
Chemical data
FormulaC25H24N6O2 
Mol. mass440.4971

Ibrutinib (USAN,[1] also known as PCI-32765 and marketed in the U.S. under the name Imbruvica) is an anticancer drug targeting B-cell malignancies. It was approved by the US FDA in November 2013 for the treatment of mantle cell lymphoma[2] and in February 2014 for the treatment of chronic lymphocytic leukemia.[3] It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase (BTK).[4][5][6] Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson's Janssen Pharmaceutical division for additional B-cell malignancies including diffuse large B-cell lymphoma and multiple myeloma.[7][8][9]

Medical uses[edit]

It is FDA-approved as a treatment for mantle cell lymphoma[10] and chronic lymphocytic leukemia.[3]

Adverse effects[edit]

Adverse effects by incidence:[10][11]

Very common (>10% frequency):

  • Increased serum creatinine
  • Thrombocytopaenia
  • Diarrhoea
  • Haemorrhage
  • Neutropaenia
  • Anaemia
  • Fatigue
  • Musculoskeletal pain
  • Peripheral oedema
  • URI infection
  • Nausea
  • Bruising
  • Dyspnoea
  • Constipation
  • Rash
  • Abdominal pain
  • Vomiting
  • Decreased appetite
  • Cough
  • Pyrexia
  • Stomatitis
  • UTI infection
  • Pneumonia
  • Skin infections
  • Asthenia
  • Muscle spasms
  • Dizziness
  • Sinusitis
  • Headache
  • Dehydration
  • Dyspepsia (indigestion)
  • Petechiae
  • Arthralgia
  • Epistaxis (nosebleeds)

Common (1-10% frequency):

Mechanism[edit]

In preclinical studies on chronic lymphocytic leukemia (CLL) cells, ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment.[12] In this study, treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk tyrosine phosphorylation and also effectively abrogated downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, ibrutinib inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.

In early clinical studies, the activity of ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments.[13]

Ibrutinib has been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor.[14][15] Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumour microenvironments.

History[edit]

Ibrutinib was first designed and synthesized at Celera Genomics which reported in 2007 a structure-based approach for creating a series of small molecules that inactivate BTK through covalent binding to cysteine-481 near the ATP binding domain of BTK.[4] These small molecules irreversibly inhibited BTK by using a Michael acceptor for binding to the target cysteine. In April 2006, Pharmacyclics acquired Celera’s small molecule BTK inhibitor discovery program, which included a compound, PCI-32765 that was subsequently chosen for further preclinical development based on the discovery of anti-lymphoma properties in vivo.[16] Since 2006, Pharmacyclics’ scientists have advanced the molecule into clinical trials and identified specific clinical indications for the drug. It also has potential effects against autoimmune arthritis.[17] It was approved by the US FDA on November 13, 2013 for the treatment of mantle cell lymphoma.[2] On Feb. 12, 2014, the U.S. Food and Drug Administration expanded the approved use of the drug ibrutinib to chronic lymphocytic leukemia (CLL).,[18] and further expansion to 17p deletion in CLL were approved the 28th of July 2014.

References[edit]

  1. ^ Statement on a Nonproprietary Name Adopted by the USAN Council
  2. ^ a b FDA Press Release
  3. ^ a b Azvolinsky, PhD, Anna. "FDA Approves Ibrutinib for Chronic Lymphocytic Leukemia". Cancer Network. Retrieved 14 February 2014. 
  4. ^ a b Pan, Z; Scheerens, H; Li, SJ; Schultz, BE; Sprengeler, PA; Burrill, LC; Mendonca, RV; Sweeney, MD; Scott, KC; Grothaus, Paul G.; Jeffery, Douglas A.; Spoerke, Jill M.; Honigberg, Lee A.; Young, Peter R.; Dalrymple, Stacie A.; Palmer, James T. (2007). "Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase". ChemMedChem 2 (1): 58–61. doi:10.1002/cmdc.200600221. PMID 17154430. 
  5. ^ Celera Genomics Announces Sale of Therapeutic Programs to Pharmacyclics
  6. ^ United States patent 7514444
  7. ^ Janssen Biotech, Inc. Announces Collaborative Development and Worldwide License Agreement for Investigational Anti-Cancer Drug, PCI-32765
  8. ^ Clinical trials involve PCI-32765
  9. ^ Clinical trials involve ibrutinib
  10. ^ a b "Imbruvica (Ibrutinib)". Medscape Reference. WebMD. Retrieved 13 January 2014. 
  11. ^ "IMBRUVICA (ibrutinib) capsule [Pharmacyclics, Inc]". DailyMed. Pharmacyclics, Inc. November 2013. Retrieved 13 January 2013. 
  12. ^ Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, Flynn J, Jones J, Blum KA, Buggy J.J., Hamdy A, Johnson AJ, Byrd JC, SE (2011). "Bruton's tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765". Blood 117 (23): 6287–6296. doi:10.1182/blood-2011-01-328484. PMC 3122947. PMID 21422473. 
  13. ^ The Bruton's tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study" J Clin Oncol 30, 2012 (suppl; abstr 6507)
  14. ^ Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, Burger JA (2012). The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo 119. Blood. pp. 1182–1189. 
  15. ^ de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M (2012). "The clinically active BTK inhibitor PCI-32765 targets B-cell receptor (BCR)- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia". Blood 2012: 2590–2594. 
  16. ^ Honigberg, LA; Smith, AM; Sirisawad, M; Verner, E; Loury, D; Chang, B; Li, S; Pan, Z; Thamm, DH; Miller, RA; Buggy, JJ (2010). "The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy". Proceedings of the National Academy of Sciences of the United States of America 107 (29): 13075–80. doi:10.1073/pnas.1004594107. PMC 2919935. PMID 20615965. 
  17. ^ Chang, BY; Huang, MM; Francesco, M; Chen, J; Sokolove, J; Magadala, P; Robinson, WH; Buggy, JJ (2011). "The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells". Arthritis Research & Therapy 13 (4): R115. doi:10.1186/ar3400. PMC 3239353. PMID 21752263. 
  18. ^ http://cancer.osu.edu/mediaroom/releases/Pages/Ohio-State-Cancer-Research-Played-a-Significant-Role-in-FDA-Approval-of-Important-New-CLL-Drug.aspx#sthash.3o9uyt78.dpuf

External links[edit]