CEP-28122, a Highly Potent and Selective Orally Active Inhibitor of Anaplastic Lymphoma Kinase with Antitumor Activity in Experimental Models of Human Cancers

Anaplastic lymphoma kinase (ALK) is constitutively activated in a number of human cancer types due to chromosomal translocations, point mutations and gene amplification and has emerged as an excellent molecular target for cancer therapy. Here we report the identification and preclinical characterization of CEP-28122, a highly potent and selective orally active ALK inhibitor. CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. It induced concentration-dependent growth inhibition/cytotoxicity of ALK-positive ALCL, NSCLC and neuroblastoma cells, and displayed dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice, with substantial target inhibition (>90%) for > 12 h following single oral dosing at 30 mg/kg. Dose-dependent anti-tumor activity was observed in ALK-positive ALCL, NSCLC and neuroblastoma tumor xenografts in mice administered CEP-28122 orally, with complete/near complete tumor regressions observed following treatment at doses of 30 mg/kg b.i.d. or higher. Treatment of mice bearing Sup-M2 tumor xenografts for 4 weeks and primary human ALCL tumorgrafts for 2 weeks at 55 or 100 mg/kg b.i.d. led to sustained tumor regression in all mice, with no tumor re-emergence for > 60 days post cessation of treatment. Conversely, CEP-28122 displayed marginal anti-tumor activity against ALK-negative human tumor xenografts under the same dosing regimens. Administration of CEP-28122 was well tolerated in mice and rats. In summary, CEP-28122 is a highly potent and selective orally active ALK inhibitor with a favorable pharmaceutical and pharmacokinetic profile and robust and selective pharmacological efficacy against ALK-positive human cancer cells and tumor xenograft models in mice.

http://mct.aacrjournals.org/content/early/2011/12/30/1535-7163.MCT-11-0776.abstract

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