Abstract 5155: Orally bioavailable aurora-kinase B inhibitor (MK7) as a potential therapeutic approach in multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy diagnosed in approximately 30 thousand patients per year and accounts for nearly 12 thousand deaths in the US representing 2% of all cancer-related mortality. Novel agents have increased the survival of MM patients; however, patients with high-risk features and/or relapsed/refractory disease exhibit poor outcomes and remain an unmet, therapeutic challenge. Most patients develop refractory disease through a lack of successful mechanism-based therapies and progressive, genetic instability with copy number abnormalities. Aurora-kinase B (AURKB) is a key component of the chromosomal passenger complex (CPC), a key regulator of mitosis. The CPC ensures correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly as well as orderly cytokinesis. AURKB is a therapeutic target for many cancers but targeting attempts have been fraught with specificity and toxicity issues warranting further work to improve small molecule inhibitors. Thus, we sought to characterize the potential of MK7, a novel AURKB inhibitor, as a therapeutic approach in MM. MK7 is the first orally bioavailable AURKB inhibitor with favorable pharmacokinetic properties. Histone phosphorylation plays a direct role in major cell events, such as mitosis, cell death, repair, replication and recombination. MK7 activity can be assessed by a decrease in the levels of phosphorylation of histone H3(p-H3). First, we measured the expression of mRNA of AURKB in MM cell lines (i.e., MM1S, MM1R, U266, SKO-007, U266 lenalidomide resistant (U266-LR), AMO1, AMO1 bortezomib resistant (AMO1-BZ) and AMO1 carfilzomib resistant (AMO1-CZ) and primary CD138+ BM samples from patients with MM. In addition, we determined protein levels of AURKB and its substrate H3 (as phospho-H3) and found that all cell lines and primary samples showed detectable levels of AURKB and p-H3, including cell lines resistant to lenalidomide, bortezomib, and carfilzomib. Next, we evaluated the in vitro dose response to MK7 (5 to 0.015uM) and found a significant decrease in viability at concentrations below 125nM as early as 24 hours post-treatment in all cell lines tested (less than 50%). Furthermore, we observed dramatic changes in size and morphology as early as 6 hours post treatment. Response to MK7 was also assessed in vivo using U266-GFP/Luciferase xenografts. Mice were treated with 30 mg/kg P.O. MK7 three times a week (total 1