Data from Characterization of Alisertib (MLN8237), an Investigational Small-Molecule Inhibitor of Aurora A Kinase Using Novel <i>In Vivo</i> Pharmacodynamic Assays

Abstract

<div>Abstract<p><b>Purpose:</b> Small-molecule inhibitors of Aurora A (AAK) and B (ABK) kinases, which play important roles in mitosis, are currently being pursued in oncology clinical trials. We developed three novel assays to quantitatively measure biomarkers of AAK inhibition <i>in vivo</i>. Here, we describe preclinical characterization of alisertib (MLN8237), a selective AAK inhibitor, incorporating these novel pharmacodynamic assays.</p><p><b>Experimental Design:</b> We investigated the selectivity of alisertib for AAK and ABK and studied the antitumor and antiproliferative activity of alisertib <i>in vitro</i> and <i>in vivo</i>. Novel assays were used to assess chromosome alignment and mitotic spindle bipolarity in human tumor xenografts using immunofluorescent detection of DNA and alpha-tubulin, respectively. In addition, 18F-3′-fluoro-3′-deoxy-l-thymidine positron emission tomography (FLT-PET) was used to noninvasively measure effects of alisertib on <i>in vivo</i> tumor cell proliferation.</p><p><b>Results:</b> Alisertib inhibited AAK over ABK with a selectivity of more than 200-fold in cells and produced a dose-dependent decrease in bipolar and aligned chromosomes in the HCT-116 xenograft model, a phenotype consistent with AAK inhibition. Alisertib inhibited proliferation of human tumor cell lines <i>in vitro</i> and produced tumor growth inhibition in solid tumor xenograft models and regressions in <i>in vivo</i> lymphoma models. In addition, a dose of alisertib that caused tumor stasis, as measured by volume, resulted in a decrease in FLT uptake, suggesting that noninvasive imaging could provide value over traditional measurements of response.</p><p><b>Conclusions:</b> Alisertib is a selective and potent inhibitor of AAK. The novel methods of measuring Aurora A pathway inhibition and application of tumor imaging described here may be valuable for clinical evaluation of small-molecule inhibitors. <i>Clin Cancer Res; 17(24); 7614–24. ©2011 AACR</i>.</p></div>