CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. CEP-28122 induced concentration-dependent growth inhibition/cytotoxicity of ALK-positive anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cells, and displayed dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice. CEP-28122 displayed marginal antitumor 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 pharmacologic efficacy against ALK-positive human cancer cells and tumor xenograft models in mice.
|Cell lines||NPM-ALK–positive ALCL (Karpas-299 and Sup-M2) cells and ALK-negative lymphoma HuT-102 and leukemia Toledo cells; EML4-ALK–positive (NCI-H2228 and H3122) and EML4-ALK–negative (NCI-H1650) NSCLC cells and neuroblastoma cell lines|
|Preparation method||Cell growth inhibition
Living cells were measured with the CellTiter 96 nonradioactive cell proliferation assay (MTS assay) kit. In brief, the cells were seeded on 96-well plates and 48 to 72 hours after compound treatment, equal volume of reagents from the kit was added to the culture medium. After incubation for 1 to 4 hours, the plates were measured with a plate reader and the relative cell numbers were calculated on the basis of the standard curve.
|Concentrations||0~10 μ M|
|Incubation time||48 to 72 h|
|Animal models||SCID mice bearing NCI-H2228, NCI-H3122, and NCI-1650 (A) or NB-1 and NB-1691 (B) subcutaneous tumor xenografts|
|Formulation||PEG-400, or dH2O|
|Dosages||3, 10, or 30 mg/kg twice a day for 10 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers.
Cheng M, et al. Mol Cancer Ther. 2012 Mar;11(3):670-9. PMID: 22203728.
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