Crizotinib

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Crizotinib
File:Crizotinib structure.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
Routes of
administration		 Oral
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Biological half-life 46 hours
Identifiers
CAS Number 877399-52-5
ATC code none
PubChem CID 11626560
Synonyms PF-02341066
1066
Chemical data
Formula C21H22Cl2FN5O
Molar mass 450.337 g/mol[[Script error: No such module "String".]]
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Crizotinib (also known as PF-02341066 or 1066), is an ALK (anaplastic lymphoma kinase) inhibitor of the aminopyridine chemical series that is being developed by Pfizer Incorporated. It is currently undergoing clinical trials testing its safety and efficacy in treating several forms of cancer, particularly non-small cell lung carcinoma (NSCLC), anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.[1]

Mechanism of action

Crizotinib is an ALK (anaplastic lymphoma kinase) inhibitor under study in patients with advanced NSCLC carrying the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene. The protein product of this fusion has constitutive kinase activity that is carcinogenic.[2] Crizotinib competes with ATP for the ALK kinase domain of this fusion protein.[2] The ELM4-ALK fusion transcript was first described in a 2007 study published in Nature.[3] Not all patients with lung cancer or NSCLC carry the ELM4-ALK fusion. Patients with this gene inversion are typically non-smokers who do not have mutations in the epidermal growth factor receptor gene (EGFR) or in the KRAS gene.[2][4] Approximately 4% of the 220,000 Americans diagnosed with lung cancer each year have the ALK fusion gene, and 45,000 newly diagnosed NSCLC patients are ALK positive worldwide.[5][6]

ALK gene mutations are also thought to be important in driving the malignant phenotype in a significant percentage (15%) of cases of neuroblastoma, a rare form of nervous system cancer that occurs almost exclusively in very young children.[7]

Crizotinib is also an inhibitor of the c-Met/Hepatocyte Growth Factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of cancer.[8].

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[8][9] Other studies suggest that Crizotinib may also act via inhibition of angiogenesis in malignant tumors.[10]

Clinical trials

Researchers at the American Society of Clinical Oncology 2010 Annual Meeting presented data from an ongoing phase 1/2 study that showed crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[4][5] Tumors shrank at least 30% in 57% of the patients treated.[5] Most of the 82 patients had adenocarcinoma, and most had never smoked or were former smokers.[4] 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.[4][11] They were given 250 mg crizotinib twice daily for a median duration of six months.[4] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.[11] Those who responded to treatment have had responses that last up to 15 months thus far.[11]

That study did not have a control group, but a phase 3 trial, PROFILE 1007, will compare crizotinib with standard of care chemotherapy in the treatment of ALK-positive NSCLC.[1][6][12] Additionally, a phase 2 trial, PROFILE 1005, will study patients meeting similar criteria who have received more than one line of prior chemotherapy.[6]

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma,[8] and neuroblastoma.[13]

References

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CI monoclonal antibodies ("-mab")
Others for solid tumors
Tyrosine kinase inhibitors ("-nib")
Other
  1. ↑ 1.0 1.1 ClinicalTrials.gov NCT00932451
  2. ↑ 2.0 2.1 2.2 "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. Retrieved 2010-06-07. 
  3. ↑ "Anaplastic Lymphoma Kinase; ALK". Online Mendelian Inheritance in Man. 2009-09-21. Retrieved 2010-06-07. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. Retrieved 2010-06-07. 
  5. ↑ 5.0 5.1 5.2 "Advances Come in War on Cancer". The Wall Street Journal. 2010-06-07. Retrieved 2010-06-07. 
  6. ↑ 6.0 6.1 6.2 [http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf "Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types"] (Press release). Pfizer Oncology. 2010-05-20. http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf. Retrieved 2010-06-07. 
  7. ↑ Janoueix-Lerosey I, Schleiermacher G, Delattre O. Molecular pathogenesis of peripheral neuroblastic tumors. Oncogene 2010;29:1566-79.
  8. ↑ 8.0 8.1 8.2 http://clinicaltrials.gov/ct2/show/NCT00585195
  9. ↑ 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.
  10. ↑ 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. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 2007;67:4408-17.
  11. ↑ 11.0 11.1 11.2 "Gene-based lung cancer drug shows promise". MSNBC.com. 2010-05-07. Retrieved 2010-06-07. 
  12. ↑ ClinicalTrials.gov NCT00932893
  13. ↑ http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=35242
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