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 names Xalkori
MedlinePlus a612018
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 43%
Protein binding 91%
Metabolism Hepatic (CYP3A4/CYP3A5-mediated)
Half-life 42 hours
Excretion Faeces (63%), urine (22%)
Identifiers
CAS number 877399-52-5 N
ATC code L01XE16
PubChem CID 11626560
DrugBank DB08700
ChemSpider 9801307 YesY
UNII 53AH36668S YesY
KEGG D09731 N
ChEBI CHEBI:64310 N
ChEMBL CHEMBL601719 YesY
Synonyms PF-02341066
1066
PDB ligand ID VGH (PDBe, RCSB PDB)
Chemical data
Formula C21H22Cl2FN5O 
Mol. mass 450.337 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,[2][3][4] 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.[5]

Mechanism of action[edit]

Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2[6]

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.[7] The kinase activity of the fusion protein is inhibited by crizotinib.[7] 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.[7][8] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[9][10]

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.[11]

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.[12]

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[12][13] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.[14]

Clinical trials[edit]

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[8][9] Tumors shrank at least 30% in 57% of people treated.[9] [15] Most had adenocarcinoma, and had never smoked or were former smokers.[8] 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.[8][16] They were given 250 mg crizotinib twice daily for a median duration of six months.[8] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.[16] Some responses to crizotinib have lasted up to 15 months.[16]

A phase 3 trial, PROFILE 1007,[17] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.[5][10][18] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.[10]

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,[12] and neuroblastoma.[19]

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. 
  2. ^ Forde PM, Rudin CM (2012). "Crizotinib in the treatment of non-small-cell lung cancer". Expert Opin Pharmacother 13 (8): 1195–201. doi:10.1517/14656566.2012.688029. PMID 22594847. 
  3. ^ Roberts PJ (2013). "Clinical use of crizotinib for the treatment of non-small cell lung cancer". Biologics 7: 91–101. doi:10.2147/BTT.S29026. PMC 3643289. PMID 23671386. 
  4. ^ Sahu A, Prabhash K, Noronha V, Joshi A, Desai S (2013). "Crizotinib: A comprehensive review". South Asian J Cancer 2 (2): 91–7. doi:10.4103/2278-330X.110506. PMC 3876666. PMID 24455567. 
  5. ^ 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
  6. ^ Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, 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 RS, Edwards MP (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)". J. Med. Chem. 54 (18): 6342–63. doi:10.1021/jm2007613. PMID 21812414. 
  7. ^ a b c "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. Retrieved 2010-06-07. 
  8. ^ 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. 
  9. ^ a b c Winslow, Ron (2010-06-07). "Advances Come in War on Cancer". The Wall Street Journal. Retrieved 2010-06-07. 
  10. ^ 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. 
  11. ^ Janoueix-Lerosey I, Schleiermacher G, Delattre O (2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene 29 (11): 1566–79. doi:10.1038/onc.2009.518. PMID 20101209. 
  12. ^ a b c ClinicalTrials.gov NCT00585195 A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer
  13. ^ Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G (2007). "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. 6 (12 Pt 1): 3314–22. doi:10.1158/1535-7163.MCT-07-0365. PMID 18089725. 
  14. ^ Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, Koudriakova TB, Alton G, Cui JJ, Kung PP, Nambu MD, Los G, Bender SL, Mroczkowski B, Christensen JG (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. doi:10.1158/0008-5472.CAN-06-4443. PMID 17483355. 
  15. ^ Helwick (2010). "Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC".  NB Fig 1.
  16. ^ a b c "Gene-based lung cancer drug shows promise". MSNBC.com. 2010-05-07. Retrieved 2010-06-07. 
  17. ^ "Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling". Fact Sheet. Pfizer. 
  18. ^ ClinicalTrials.gov NCT00932893 An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
  19. ^ Wood AC, Laudenslager M, Haglund EA, Attiyeh EF, Pawel B, Courtright J, Plegaria J, Christensen JG, Maris JM, Mosse YP (2009). "Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066". J Clin Oncol. 27 (15s. suppl; abstr 10008b).