MLN8054, an orally active Aurora A kinase small molecule inhibitor in phase I clinical trials

4724 The Aurora family of mitotic kinases play key roles in proper cell cycle progression. Aurora A and Aurora B are overexpressed in several human tumors and the Aurora A gene is amplified in a variety of cancers including breast, colon, and pancreatic. Due to their role in cancer, these kinases have been pursued as potential drug targets. Small molecules that inhibit both Aurora A and Aurora B kinase have been described in the literature and three have entered clinical trials. Here, we describe the first selective inhibitor of Aurora A to enter phase I clinical trials, MLN8054. MLN8054 selectively inhibits Aurora A over Aurora B in cultured human tumor cells and treatment results in phenotypes consistent with Aurora A inhibition including accumulation of mitotic cells with spindle abnormalities, and apoptosis. MLN8054 is orally bioavailable with a favorable pharmacokinetic profile to support once a day dosing in mice. A single oral administration of MLN8054 to nude mice bearing human colon tumor lines SW480 and HCT-116 resulted in a time-dependent accumulation of mitotic cells (beginning 4 hours after treatment) as detected by immunofluorescent staining for two mitotic markers. These in vivo results are consistent with MLN8054 mediating pharmacological effects through Aurora A inhibition. MLN8054 did not inhibit Aurora B in vivo at therapeutic doses as determined by the presence of staining in tumor tissue for the Aurora B substrate phosphorylated histone H3 (Ser10). Repeat dosing of MLN8054 induced apoptosis (starting on day 3) and tumor growth inhibition in several tumor models with once or twice a day dosing. MLN8054 is the first reported selective inhibitor of Aurora A kinase that robustly inhibits growth of human tumor xenografts and represents a novel modality for therapeutic intervention of human cancers.