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Crizotinib

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Crizotinib
Clinical data
Other namesPF-02341066
1066
Routes of
administration		Oral
Identifiers
  • 3-[(1R)-1-(2, 6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.166.440 Edit this at Wikidata
Chemical and physical data
FormulaC21H22Cl2FN5O0
Molar mass450.337 g/mol g·mol−1
3D model (JSmol)
  • C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl

Crizotinib (also known as PF-02341066 or 1066), is an ALK (anaplastic lymphoma kinase) inhibitor being developed by Pfizer Incorporated. It is currently undergoing clinical trials for its potential to treat advanced non-small cell lung carcinoma (NSCLC).[1]

Mechanism of action

Crizotinib is an oral 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] Patients with this gene inversion typically non-smokers who do not have mutations in the epidermal growth factor receptor gene (EGFR) or mutations 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 annually.[5][6]

Clinical trials

Researchers at the American Society of Clinical Oncology 2010 Annual Meeting presented data from an ongoing phase 1/2 study that show crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene. Tumors shrank at least 30% in 57% of the patients treated. In the study, patients were given 250 mg twice daily. The median duration of treatment with crizotinib was 6 months. Side effects included nausea, vomiting, and diarrhea. Approximately 50% of the patients studied had at least one symptom. Most patients were never-smokers or former smokers and had adenocarcinoma. These patients had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to this prior treatment. Those who responded to therapy have had responses that last up to 15 months thus far. This study did not have a control group, but a phase 3 trial, PROFILE 1007, will compare crizotinib with stanard of care chemotherapy in the treatment of ALK-positive NSCLC. Additionally, a phase 2 trial, PROFILE 1005, will study patients meeting similar criteria who have receive more than one line of prior chemotherapy.

References

  1. ^ Clinical trial number NCT00932451 at ClinicalTrials.gov
  2. ^ a b c http://cme.medscape.com/viewarticle/720896_transcript
  3. ^ <http://www.ncbi.nlm.nih.gov/omim/105590#105590_Reference12
  4. ^ <http://www.hemonctoday.com/article.aspx?rid=65251
  5. ^ <http://online.wsj.com/article/SB10001424052748704002104575291103764336126.html?mod=WSJ_WSJ_US_News_3
  6. ^ <http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf


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