Abstract 4540: SAC abrogation by MPS1 kinase inhibition: preclinical proof of concept of a novel approach to tumor treatment

Abstract

Abstract Cell cycle deregulation represents one of the classical hallmarks of cancer and consequently cell cycle arrest is the predominant mode of action of a number of antimitotic cancer drugs (e.g. taxanes and vinca alkaloids). Targeted disruption of the cell cycle checkpoint offers a novel approach to cancer treatment: driving tumor cells into cell division despite DNA damage or unattached/misattached chromosomes resulting in a lethal degree of DNA damage or aneuploidy. MPS1, a mitotic kinase that is overexpressed in several human cancers, has been shown to function as the key kinase which activates the spindle assembly checkpoint (SAC) to secure proper distribution of chromosomes to daughter cells. Here, we report the identification and functional characterization of novel inhibitors of MPS1 from two structurally unrelated chemical classes. In biochemical assays, these molecules inhibited the kinase activity of MPS1 with IC50 values in the single digit nanomolar range and have shown an exquisite selectivity against a panel of kinases. In cellular assays the compounds were able to abrogate nocodazole-induced SAC, to reduce time in mitosis, to induce multinuclearity and apoptotic cell death, and to inhibit tumor cell proliferation with IC50 values in the low nanomolar range. In combination experiments MPS1 inhibitors showed cooperativity with low concentrations of paclitaxel. MPS1 inhibitors showed limited efficacy in monotherapy (T/C ca. 0.6) in tumor xenograft studies. However, when combined with paclitaxel dosed at the maximal tolerated dose, low doses of MPS1 inhibitor strongly improved efficacy over paclitaxel or MPS inhibitor monotreatment in intrinsically paclitaxel-insensitive xenograft models. The combination treatment was well tolerated. These results validate the concept of SAC abrogation preclinically and pave the way to a clinical proof of concept. Citation Format: Dominik Mumberg, Gerhard Siemeister, Antje M. Wengner, Marcus Koppitz, Volker Schulze, Benjamin Bader, Stefan Prechtl, Bertolt Kreft, Karl Ziegelbauer. SAC abrogation by MPS1 kinase inhibition: preclinical proof of concept of a novel approach to tumor treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4540. doi:10.1158/1538-7445.AM2014-4540