MLN8237: an orally active small molecule inhibitor of Aurora A kinase in phase I clinical trials

237 Aurora A kinase regulates the activity of a number of proteins essential to the proper execution of mitosis. Perturbation of Aurora A results in aberrant mitoses leading to cell death. We have developed a selective Aurora A kinase inhibitor, MLN8237; to be used for the therapeutic intervention of human cancers. MLN8237 displays potent activity against Aurora A in both enzymes and cell assays. In cells, MLN8237 proved to be more than 200 fold more selective for Aurora A than the structurally related kinase Aurora B. Treatment of cultured human tumor cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, inhibition of cell proliferation and apoptosis. MLN8237 is orally bioavailable and has a favorable pharmacokinetic profile. A single oral administration of MLN8237 to nude mice bearing subcutaneous human tumor xenografts resulted in a time dependent accumulation of mitotic cells, consistent with the pharmacological effect being mediated through Aurora A inhibition. Repeat oral administration of MLN8237 at well tolerated doses to nude mice bearing subcutaneous human tumor xenografts resulted in dramatic tumor growth inhibition in all models evaluated. In these models, MLN8237 induced mitotic accumulation and apoptosis. MLN8237 did not appreciably inhibit Aurora B at efficacious concentrations, as indicated by measuring phosphorylated histone H3 Ser10 staining. MLN8237 is currently in Phase I clinical trials in patients with advanced malignancies.