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 Experiment | |
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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 Experiment | |
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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 |
Administration | oral |
Molecular Weight | 539.07 |
Formula | C28H35ClN6O3 |
CAS Number | 1022958-60-6 |
Solubility (25°C) | DMF: 10 mg/mL |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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