Abstract 1818: the Aurora B Inhibitor ABT-348 is Not Susceptible to Known Resistance Mechanisms of Other Aurora B Inhibitors

Abstract The Aurora kinases (Aurora A, B, and C) play essential roles in regulating cell division in mammalian cells and their over-expression in diverse tumor types makes them appealing oncology targets. ABT-348 is a novel, ATP-competitive, multi-targeted kinase inhibitor that exhibits potent activity in multiple solid tumor-derived and leukemia cell lines. ABT-348 is active against Aurora B (IC50 7 nM) and Aurora C (IC50 1 nM), Aurora A (IC50 120 nM). The activity against Aurora B is demonstrated by inhibition of histone H3 phosphorylation and induction of polyploidy. ABT-348 is also active against Aurora-B Y156H, a mutant resistant to other Aurora-B inhibitors. In addition, ABT-348 potently inhibits most members of the VEGFR and PDGFR family of receptor tyrosine kinases, which play a critical role in stromal angiogenesis. In contrast to other Aurora kinase inhibitors, the cellular efficacy of ABT-348 is retained in cells over-expressing P-glycoprotein (Pgp) or breast cancer resistant protein (BCRP), indicating that ABT-348 is not a substrate for these commonly upregulated ATP-binding cassette drug transporters. Consistent with these in vitro studies, ABT-348 was broadly efficacious as a single agent against a wide range of tumor types in vivo, including 3 multi-drug resistant xenograft models. In summary, the potent activity and unique kinase selectivity of ABT-348 against the Aurora kinases and VEGF and PDGF receptor tyrosine kinases, engender its ability to block multiple mechanisms of tumor progression. In addition, our data provide evidence that ABT-348 may be active in tumors resistant to other well-characterized inhibitors targeting Aurora-B. ABT-348 is presently under clinical evaluation in adult patients with advanced solid and hematological neoplasms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1818. doi:1538-7445.AM2012-1818