Abstract 3090: Novel Mps1 kinase inhibitors with potent anti-tumor activity
Authors: Wengner Antje Margret , Siemeister Gerhard , Koppitz Marcus , Schulze Volker , Kosemund Dirk , Klar Ulrich , Stoeckigt Detlef , Neuhaus Roland , Lienau Philip , Bader Benjamin , Prechtl Stefan , Doehr Olaf , Raschke Marian , von Ahsen Oliver , Elbi Cem , Bruns Ingmar , Michels Martin , Kreft Bertolt , von Nussbaum Franz , Brands Michael , Mumberg Dominik , Ziegelbauer Karl 
Published: August 2015

Abstract
Cell cycle deregulation represents one of the hallmarks of cancer and consequently cell cycle arrest is the predominant mode of action for 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 since tumor cells will not arrest in mitosis despite DNA damage or unattached/misattached chromosomes resulting in aneuploidy and cell death. 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 disclose for the first time the structure and functional characterization of two novel Mps1 inhibitors, BAY 1161909 and BAY 1217389, derived from structurally distinct chemical classes. BAY 1161909 and BAY 1217389 inhibited Mps1 kinase activity with IC50 values below 10 nM while showing an excellent selectivity profile against a broad panel of kinases. In cellular mechanistic assays, BAY 1161909 and BAY 1217389 abrogated nocodazole-induced SAC activity, inducing premature exit from mitosis (“mitotic breakthrough”), which results in multinuclearity and tumor cell death. Both compounds efficiently inhibited tumor cell proliferation in vitro (IC50 values in low nanomolar range), showing a similar inhibitory pattern in a broad panel of tumor cell lines. In vivo, the Mps1 inhibitors BAY 1161909 and BAY 1217389 achieved moderate efficacy in monotherapy in tumor xenograft studies (tumor growth inhibition ∼ 50%). However, according to its unique mode of action, when combined with paclitaxel, at the maximum tolerated dose, low doses of Mps1 inhibitor reduced paclitaxel-induced mitotic arrest in line with weakening of SAC activity. Consequently, combination therapy strongly improved efficacy over paclitaxel or Mps1 inhibitor mono-treatment in a broad range of xenograft models including those being intrinsically paclitaxel-insensitive as well as those with acquired paclitaxel resistance. Both Mps1 inhibitors showed good tolerability without adding toxicity to paclitaxel monotherapy.
Our findings validate the innovative concept of SAC abrogation and justify clinical proof of concept studies evaluating Mps1 inhibitors BAY 1161909 and BAY 1217389 in combination with antimitotic cancer drugs in order to enhance their efficacy and potentially overcome resistance. BAY 1161909 is currently in a phase I clinical trial (NCT02138812), start of clinical investigation of BAY 1217389 is planned. To our knowledge BAY 1161909 and BAY 1217389 are the first Mps1 inhibitors in clinical trials.
Citation Format: Antje Margret Wengner, Gerhard Siemeister, Marcus Koppitz, Volker Schulze, Dirk Kosemund, Ulrich Klar, Detlef Stoeckigt, Roland Neuhaus, Philip Lienau, Benjamin Bader, Stefan Prechtl, Olaf Doehr, Marian Raschke, Oliver von Ahsen, Cem Elbi, Ingmar Bruns, Martin Michels, Bertolt Kreft, Franz von Nussbaum, Michael Brands, Dominik Mumberg, Karl Ziegelbauer. Novel Mps1 kinase inhibitors with potent anti-tumor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3090. doi:10.1158/1538-7445.AM2015-3090