MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors

The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (<b>8</b>) and alisertib (MLN8237, <b>10</b>) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (<b>10</b>) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors

Discovery of a Potent and Orally Bioavailable Benzolactam-Derived Inhibitor of Polo-Like Kinase 1 (MLN0905)

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (<b>12c</b>, MLN0905). In vivo pharmacokinetic–pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of <b>12c</b> to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model