Abstract 706: Novel MPS1 inhibitors with potential anticancer activity.
Authors: Wengner Antje , Jemaà Mohamed , Galluzzi Lorenzo , Kepp Oliver , Brands Michael , Koppitz Marcus , Schulze Volker , Siemeister Gerhard , Mumberg Dominik , Ziegelbauer Karl , Castedo Maria , Vitale Ilio , Kroemer Guido 
Published: August 2014

Abstract
MPS1, a mitotic kinase that is overexpressed in several human cancers, has been shown to contribute to the alignment of chromosomes to the metaphase plate, as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 from two structurally independent chemical classes, Mps-BAY1, Mps-BAY2a and Mps-BAY2b. In biochemical assays, these molecules inhibited the kinase activity of MPS1 with IC50 values in the low nanomolar range. By selectively inactivating MPS1, these small molecule inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or cell death. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation, and severe anaphase defects. Videomicroscopic cell fate profiling of GFP-histone 2B-expressing cells revealed the capacity of MPS1 inhibitors to subvert mitotic timing by inducing a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) fashion or entered one or more rounds of abortive mitosis, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed from the mitotic catastrophe-induced activation of the intrinsic pathway of apoptosis. Of note, MPS1 inhibitors and paclitaxel (a microtubular poison) combined at low doses synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization, followed by the activation of mitotic catastrophe. A more than additive interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo in a HeLa-Matu human cervical xenograft model. The combination of these agents reduced the mitotic index in xenograft tumors and exerted superior antineoplastic effects (T/C 0.04) as compared to the administration of vehicle, as well as paclitaxel (T/C 0.38) or MPS inhibitor (T/C 0.51) alone. Altogether, these results suggest that MPS1 inhibitors may have potent anticancer activity, either as standalone agents or in combination with microtubule-targeting agents.
Citation Format: Antje Wengner, Mohamed Jemaà, Lorenzo Galluzzi, Oliver Kepp, Michael Brands, Marcus Koppitz, Volker Schulze, Gerhard Siemeister, Dominik Mumberg, Karl Ziegelbauer, Maria Castedo, Ilio Vitale, Guido Kroemer. Novel MPS1 inhibitors with potential anticancer activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 706. doi:10.1158/1538-7445.AM2013-706