Crizotinib

From Infogalactic: the planetary knowledge core
Jump to: navigation, search
Crizotinib
Crizotinib.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
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability 43%
Protein binding 91%
Metabolism Hepatic (CYP3A4/CYP3A5-mediated)
Biological half-life 42 hours
Excretion Faeces (63%), urine (22%)
Identifiers
CAS Number 877399-52-5 N
ATC code L01XE16 (WHO)
PubChem CID: 11626560
IUPHAR/BPS 4903
DrugBank DB08700 YesY
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
Molecular mass 450.337 g/mol
  • C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl
  • InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1 YesY
  • Key:KTEIFNKAUNYNJU-GFCCVEGCSA-N YesY
 NYesY (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

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]

Approvals and indications

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.

Clinical trials

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]

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma,[12] and neuroblastoma.[19]

See also

References

  1. ↑ 1.0 1.1 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 Clinical trial number NCT00932451 for "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" at ClinicalTrials.gov
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 7.2 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 9.2 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.0 10.1 10.2 Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 12.2 Clinical trial number NCT00585195 for "A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer" at ClinicalTrials.gov
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found. NB Fig 1.
  16. ↑ 16.0 16.1 16.2 Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Clinical trial number NCT00932893 for "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" at ClinicalTrials.gov
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
Retrieved from "https://infogalactic.com/w/index.php?title=Crizotinib&oldid=722603011"