Abstract 3642: Structure enabled design of inhibitors of the mitotic kinase MPS1

Abstract MPS1 (also known as TTK), is a dual-specificity protein kinase that is essential for the proper attachment of chromosomes to the mitotic spindle. MPS1 expression is elevated in a variety of human cancers and is correlated with higher histological grade, aggressiveness and poor patient survival. It has been also shown that basal, PTEN-deficient and triple negative breast cancers are sensitive to MPS1 inhibition. These data together provide strong support for selective antitumour action of MPS1 inhibitors in human cancers. Here we report the discovery of pyridopyrimidines as a new class of inhibitors of MPS1 exploring a hybridization approach. Rapid structure based optimisation of the initial hits led to highly potent, selective and ligand efficient compounds. We will discuss our initial design approach and the structural features that are critical for potent biochemical and cellular inhibition as derived from SAR and co-crystal structures. Furthermore, we will report pharmacokinetic and in vivo properties of selected compounds and comment on our strategy to optimise this series towards preclinical candidates. Citation Format: Paolo Innocenti, Hannah Woodward, Kwai_Ming J. Cheung, Sébastien Naud, Savade Solanki, Isaac M. Westwood, Amir Faisal, Angela Hayes, Jessica Schmitt, Ross Baker, Berry Matijssen, Rosemary Burke, Suzanne A. Eccles, Florence I. Raynaud, Spiros Linardopoulos, Julian Blagg, Rob L M van Montfort, Swen Hoelder. Structure enabled design of inhibitors of the mitotic kinase MPS1. [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 3642. doi:10.1158/1538-7445.AM2015-3642