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Home > A. Molecular pathology > Targeted therapy > Small molecules > crizotinib


Thursday 10 June 2010

Pfizer drug crizotinibPF-02341066 or 1066, PF-02341066, Xalkori


Molecular target: ALK

Definition: Crizotinib is an ALK inhibitor , ROS1 inhibitor and MET inhibitor .

Crizotinib is undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, advanced non-small cell lung carcinoma (NSCLC ).

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.

Mechanism of action

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, which results in constitutive kinase activity that contributes to carcinogenesis.

The protein product of this fusion has constitutive kinase activity that is carcinogenic. Crizotinib competes with ATP for the ALK kinase domain of this fusion protein.

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.

Other studies suggest that Crizotinib may also act via inhibition of angiogenesis in malignant tumors.

Targeted therapy

- ALK-rearranged tumors

  • ALK-rearranged non-small cell lung carcinoma (NSCLC)
  • ALK-rearranged anaplastic large cell lymphoma (ALCL)
  • ALK-EML4-assoiated tumors

- ALK- mutated tumors

  • ALK-mutated neuroblastoma
    • ALK mutations are also thought to be important in driving the malignant phenotype in about 15% of cases of Neuroblastoma, a rare form of nervous system cancer that occurs almost exclusively in very young children.

- MET-amplified tumors and MET-overexpressed tumors

  • Crizotinib also 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 cancer.

See also

- ALK-ELM4 gene fusion

See also

- ALK gene
- ALK-inhibitors


- Wikipedia