Crizotinib

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Crizotinib
Crizotinib2DACS.svg
Systematic (IUPAC) name
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Clinical data
Trade namesXalkori
MedlinePlusa612018
Licence dataEMA:Link, US FDA:link
Pregnancy cat.D (AU) D (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailability43%
Protein binding91%
MetabolismHepatic (CYP3A4/CYP3A5-mediated)
Half-life42 hours
ExcretionFaeces (63%), urine (22%)
Identifiers
CAS number877399-52-5 N
ATC codeL01XE16
PubChemCID 11626560
DrugBankDB08700
ChemSpider9801307 YesY
UNII53AH36668S YesY
KEGGD09731 N
ChEBICHEBI:64310 N
ChEMBLCHEMBL601719 YesY
SynonymsPF-02341066
1066
PDB ligand IDVGH (PDBe, RCSB PDB)
Chemical data
FormulaC21H22Cl2FN5O 
Mol. mass450.337 g/mol
 N (what is this?)  (verify)
 
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Crizotinib
Crizotinib2DACS.svg
Systematic (IUPAC) name
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Clinical data
Trade namesXalkori
MedlinePlusa612018
Licence dataEMA:Link, US FDA:link
Pregnancy cat.D (AU) D (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailability43%
Protein binding91%
MetabolismHepatic (CYP3A4/CYP3A5-mediated)
Half-life42 hours
ExcretionFaeces (63%), urine (22%)
Identifiers
CAS number877399-52-5 N
ATC codeL01XE16
PubChemCID 11626560
DrugBankDB08700
ChemSpider9801307 YesY
UNII53AH36668S YesY
KEGGD09731 N
ChEBICHEBI:64310 N
ChEMBLCHEMBL601719 YesY
SynonymsPF-02341066
1066
PDB ligand IDVGH (PDBe, RCSB PDB)
Chemical data
FormulaC21H22Cl2FN5O 
Mol. mass450.337 g/mol
 N (what is this?)  (verify)

Crizotinib (trade name Xalkori,[1] Pfizer), is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.[2]

Mechanism of action[edit]

Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2[3]

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. About 4% of patients with non-small cell lung carcinoma have a chromosomal rearrangement that generates a fusion gene between EML4 ('echinoderm microtubule-associated protein-like 4') and ALK ('anaplastic lymphoma kinase'), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype.[4] The kinase activity of the fusion protein is inhibited by crizotinib.[4] Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-Ras gene.[4][5] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[6][7]

ALK mutations are thought to be important in driving the malignant phenotype in about 15% of cases of neuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.[8]

Crizotinib inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.[9]

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[9][10] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.[11]

Clinical trials[edit]

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[5][6] Tumors shrank at least 30% in 57% of people treated.[6] [12] Most had adenocarcinoma, and had never smoked or were former smokers.[5] They had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to standard therapy.[5][13] They were given 250 mg crizotinib twice daily for a median duration of six months.[5] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.[13] Some responses to crizotinib have lasted up to 15 months.[13]

A phase 3 trial, PROFILE 1007,[14] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.[2][7][15] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.[7]

On August 26, 2011, the U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.[1] Approval required a companion molecular test for the EML4-ALK fusion.

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma,[9] and neuroblastoma.[16]

See also[edit]

References[edit]

  1. ^ a b FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. U.S. Food and Drug Administration.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm
  2. ^ a b ClinicalTrials.gov NCT00932451 An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
  3. ^ Cui, J. J.; Tran-Dubé, M.; Shen, H.; Nambu, M.; Kung, P. P.; Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.; McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.; Alton, G.; Timofeevski, S.; Yamazaki, S.; Li, Q.; Zou, H.; Christensen, J.; Mroczkowski, B.; Bender, S.; Kania, R. S.; Edwards, M. P. (2011). "Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal–Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)". Journal of Medicinal Chemistry 54 (18): 6342–6363. doi:10.1021/jm2007613. PMID 21812414.  edit
  4. ^ a b c "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. Retrieved 2010-06-07. 
  5. ^ a b c d e "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. Retrieved 2010-06-07. 
  6. ^ a b c Winslow, Ron (2010-06-07). "Advances Come in War on Cancer". The Wall Street Journal. Retrieved 2010-06-07. 
  7. ^ a b c "Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types" (Press release). Pfizer Oncology. 2010-05-20. Retrieved 2010-06-07. 
  8. ^ Janoueix-Lerosey I, Schleiermacher G, Delattre O. Molecular pathogenesis of peripheral neuroblastic tumors. Oncogene 2010;29:1566-79.
  9. ^ a b c http://clinicaltrials.gov/ct2/show/NCT00585195 A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer
  10. ^ Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007;6:3314-22.
  11. ^ Zou HY, Li Q, Lee JH, Arango ME, et al. (2007). "An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.". Cancer Res 67 (9): 4408–17. 
  12. ^ Helwick (2010). "Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC".  NB Fig 1.
  13. ^ a b c "Gene-based lung cancer drug shows promise". MSNBC.com. 2010-05-07. Retrieved 2010-06-07. 
  14. ^ http://www.pfizer.com/files/news/asco/crizotinib_pf_02341066_1007_trial_bkgder_2010.pdf
  15. ^ ClinicalTrials.gov NCT00932893
  16. ^ "Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066.". 2009.