Abstract B241: Targeting the Mitotic Checkpoint with NMS-P153, a Novel MPS1 Kinase Inhibitor.

Abstract Aneuploidy is one of the major hallmarks of cancer and is a unique property of tumoral cells. Thus, targeting the molecular mechanisms required for the growth of aneuploid cells might be expected to yield more cancer cell specific therapeutic approaches. The Spindle Assembly Checkpoint (SAC) is a mitotic mechanism required for proper chromosomal segregation, ensuring that cells do not divide until all sister chromatids correctly align to the metaphase plate. It is a complex machinery tightly regulated by a number of members which are rarely mutated in tumors. Rather, checkpoint components have been found to be upregulated in aneuploid tumor cells, suggesting a potential tumor “addiction” to SAC functions. MPS1 kinase, (also known as TTK) is an essential SAC enzyme aberrantly overexpressed in a wide range of tumors and necessary for tumor cell proliferation. We previously reported the identification of NMS-P715 as a selective and orally bioavailable MPS1 inhibitor capable of promoting mitotic acceleration, thereby causing aneuploidy and cancer cell death both in vitro and in vivo. Supported by the proof that MPS1 small-molecule inhibitors display the expected mechanism of action and promote tumor growth inhibition in preclinical cancer models, further medicinal chemistry efforts were undertaken and led to the discovery of NMS-P153 as an early candidate product. NMS-P153 is highly selective, and compared to NMS-P715, shows improved in vitro enzymatic potency on MPS1 (IC50 of 3 nM), 10-fold increased mitotic override activity, longer dissociation half-life and better mouse and rat PK parameters, leading to impressive tumor growth inhibition associated with tumor regression in efficacy studies. Proliferation data performed on a large panel of cell lines (>100) have been obtained and will be essential to decipher the most sensitive genetic backgrounds to chemical abrogation of MPS1 function. In addition, single and repeated toxicology studies in rat are being carried out to establish therapeutic safety margins. Inhibiting the spindle assembly checkpoint by targeting MPS1 kinase could represent a promising new approach to cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B241.