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ALK inhibitors

Wednesday 3 February 2010

The anaplastic lymphoma kinase (ALK) is a validated target for the therapy of different malignancies.

Aberrant expression of constitutively active ALK chimeric proteins has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL) and has been detected in other cancers such as inflammatory myofibroblastic tumors, diffuse large B-cell lymphomas, certain non-small-cell lung cancers, rhabdomyosarcomas, neuroblastomas and glioblastomas.

- crizotinib (PF-02341066 or PF-1066)
- F91873
- F91874

F91873 and F91874 (19322071)

Two pyridoisoquinoline derivatives F91873 and F91874 were identified as multikinase inhibitors with activity against ALK in a biochemical screen.

F91873 and F91874 also inhibited nucleophosmin-ALK and signal transducer and activator of transcription 3 phosphorylation in the ALCL cell line COST with the same potency.

Both F91873 and F91874 behaved as ATP noncompetitive inhibitors and inhibited cell proliferation of the ALK(+) ALCL cell lines COST, PIO, and Karpas299 ALCL.

This growth inhibition effect was associated with a G1-phase cell cycle arrest.

Furthermore, administration of F91874 to severe combined immunodeficient mice bearing COST tumor xenografts resulted in a significant antitumor efficacy at 15 mg/kg/day, illustrating the potential utility of such compounds in the treatment of ALK-related pathologies.


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. Crizotinib competes with ATP for the ALK kinase domain of this fusion protein.

The ELM4-ALK fusion transcript was first described in a 2007 study published in Nature. 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 mutations in the KRAS gene.

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.

Resistance to ALK inhibitors

- (Lovly, 2012)


- Centre de Recherche en Oncologie ExpĂ©rimentale, Institut de Recherche Pierre Fabre, Toulouse Cedex 4, France. (19322071)


- Escaping ALK Inhibition: Mechanisms of and Strategies to Overcome Resistance,

- Antitumor activity of pyridoisoquinoline derivatives F91873 and F91874, novel multikinase inhibitors with activity against the anaplastic lymphoma kinase. Kruczynski A, Mayer P, Marchand A, VispĂ© S, Fournier E, Annereau JP, Brel V, Barret JM, Delsol G, Imbert T, Fahy J, Bailly C. Anticancer Drugs. 2009 Jun;20(5):364-72. PMID: 19322071