Abstract 193: Inhibitors of MPS1: Discovery of CCT289346, a highly potent, selective and orally available preclinical candidate

Abstract

Abstract MPS1 (also known as TTK), is a dual-specificity protein kinase and one of the main components of the spindle assembly checkpoint. Cancer cells heavily rely on MPS1 to cope with aneuploidy resulting from aberrant numbers of chromosomes and MPS1 has been found to be upregulated in a large number of tumor types. Extensive work by us and other groups has shown that MPS1 inhibitors are effective against a variety of cancers, particularly when used in combination with other drugs, for example, tubulin-targeting agents. We recently reported the structure-based design and discovery of a series of pyrido[3,4-d]pyrimidines inhibitors of MPS1 (1). Advanced compounds showed very potent inhibition of MPS1 in biochemical and cellular assays. However, these compounds suffered from high lipophilicity and pronounced metabolism in human liver microsomes preventing progression into preclinical development. Here we report the optimisation of this series ultimately yielding CCT289346, our preclinical candidate. CCT289346 shows excellent potency, kinase selectivity, and ADME properties including stability in human liver microsomes. The compound has been produced on a kilogram scale and is currently undergoing preclinical development. We will discuss our design approach and hypotheses leading to the discovery of CCT289346 and disclose in vivo efficacy data.