Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase

Abstract

Increased Aurora A expression occurs in a variety of human cancers and induces chromosomal abnormalities during mitosis associated with tumor initiation and progression. MLN8054 is a selective smallmolecule Aurora A kinase inhibitor that has entered Phase I clinical trials for advanced solid tumors. MLN8054 inhibits recombinant Aurora A kinase activity in vitro and is selective for Aurora A over the family member Aurora B in cultured cells. MLN8054 treatment results in G2/M accumulation and spindle defects and inhibits proliferation in multiple cultured human tumor cells lines. Growth of human tumor xenografts in nude mice was dramatically inhibited after oral administration of MLN8054 at well tolerated doses. Moreover, the tumor growth inhibition was sustained after discontinuing MLN8054 treatment. In human tumor xenografts, MLN8054 induced mitotic accumulation and apoptosis, phenotypes consistent with inhibition of Aurora A. MLN8054 is a selective inhibitor of Aurora A kinase that robustly inhibits growth of human tumor xenografts and represents an attractive modality for therapeutic intervention of human cancers.cancer ͉ mitosis ͉ apoptosis

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

“…Third, we observe that the Aurora A inhibitor MLN8054 prevents mitotic phosphorylation of BimEL on S93/94/98 and stabilizes the protein. MLN8054 inhibits Aurora A with 40-fold selectivity over Aurora B, 46 indicating that Aurora A is the main kinase being affected in our experiments. Aurora A is overexpressed in a wide range of tumor types and has been demonstrated to enhance tumor cell growth both in vivo and in vitro.…”

Mitotic drivers—inhibitors of the Aurora B Kinase

“…Subsequently, a selective Aurora A inhibitor has been described, namely MLN8054. Developed by Millennium Pharmaceuticals, MLN8054 has a benzazepine core scaffold with a fused aminopyrimidine ring and represents the first Aurora inhibitor with substantial selectivity for Aurora A over B having in vitro IC 50 values of 4 and 172 nM, respectively [31]. In cell culture assays MLN8054 also shows selectivity for Aurora A over B.…”

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

“…Several small-molecule inhibitors have been developed including Hesperadin, ZM447439, VX-680/MK0457, AZD1152 and MLN8054. [6][7][8][9] AZD1152 is a novel acetanilide-substituted pyrazole-aminoquinazoline prodrug that is rapidly converted to the active drug, AZD1152 HQPA, in human plasma. 10 AZD1152 HQPA is a highly potent and selective inhibitor of Aurora B (K i of 0.36 nM) compared to Aurora A (K i of 1369 nM) and is inactive against a panel of 50 other kinases.…”