ALK inhibitors

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

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)

Labs

 Centre de Recherche en Oncologie Expérimentale, Institut de Recherche Pierre Fabre, Toulouse Cedex 4, France. anna.kruczynski@pierre-fabre.com (#19322071#)

References

 Escaping ALK Inhibition: Mechanisms of and Strategies to Overcome Resistance, http://stm.sciencemag.org/content/4/120/120ps2.abstract

 Antitumor activity of pyridoisoquinoline derivatives F91873 and F91874, novel multikinase inhibitors with activity against the anaplastic lymphoma kinase. Kruczynski A, Mayer P, Marchand A, Vispé 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#