Abstract 2097: Targeting aneuploidy with NMS-P153, a tight binder inhibitor of the spindle assembly checkpoint MPS1 (TTK) kinase.

Abstract

Abstract Aneuploidy is one of the major hallmarks of cancer and is a unique property of tumoral cells. Targeting of the molecular mechanisms required for growth of aneuploid cells is a potential strategy for developing new therapies with preferential activity against cancer. 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. The SAC is a complex machinery 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 enzyme of the SAC complex which is aberrantly overexpressed in a wide range of tumors and necessary for tumor cell proliferation. We previously reported the identification of NMS-P715, a selective and orally bioavailable MPS1 inhibitor, capable of promoting mitotic acceleration, thereby causing massive aneuploidy and cancer cell death both in vitro and in vivo and which promotes tumor growth inhibition in preclinical cancer models. Supported by these results, a lead optimization program was then undertaken which led to the identification of NMS-P153, an optimized product candidate for clinical development. NMS-P153 is selective, shows high in vitro enzymatic potency on MPS1 (IC50 of 3 nM) and a prolonged residence binding time. More than 100 cell lines have been analyzed against NMS-P153 in proliferation studies and several distinct xenograft models have been tested in vivo, allowing the identification of potential genetic contexts of sensitivity. Potent anti-proliferative activity, good tumor growth inhibition associated with tumor regression and biomarker modulation was observed in sensitive xenograft models. A favorable ADME profile, associated with permissive therapeutic safety margins observed in different species at efficacious exposures, indicate that NMS-P153 is suitable for further development, with the potential for being a first-in-class drug targeting MPS1 kinase. Citation Format: Riccardo Colombo, Marina Caldarelli, Maria Laura Giorgini, Anna Degrassi, Marina Ciomei, Daniele Pezzetta, Dario Ballinari, Alessia Montagnoli, Enrico Pesenti, Daniele Donati, Arturo Galvani. Targeting aneuploidy with NMS-P153, a tight binder inhibitor of the spindle assembly checkpoint MPS1 (TTK) kinase. [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 2097. doi:10.1158/1538-7445.AM2013-2097