Identification of selective inhibitors of the spindle assembly checkpoint kinase TTK (Mps1) for treatment of triple negative breast cancer

Abstract

The protein kinase TTK (commonly referred to as Mps1) is a component of the Spindle Assembly Checkpoint (SAC), a surveillance mechanism that ensures the fidelity of chromosome segregation. Defects in SAC functioning can lead to chromosome segregation errors, resulting in an abnormal number of chromosomes, or 'aneuploidy'. Aneuploidy is a common feature of solid human tumors and a predictor of poor prognosis in breast, lung, brain and colorectal cancer. TTK mRNA levels are elevated in several cancers, in particular in triple negative breast cancer (TNBC), the most aggressive type of breast cancer.A novel class of compounds that potently inhibits TTK enzyme activity and cancer cell line proliferation was identified and optimized on selectivity by EntropySelect™ [1]. The clinical candidate, NTRC 0066-0, inhibits TTK enzyme activity with subnanomolar potency (IC50) and was more than 250 times selective over 276 kinases examined, including mitotic and cell cycle dependent kinases (CDKs). The compound is characterized by slow dissociation kinetics, resulting in a long target residence time. It potently inhibits the proliferation of a wide variety of human cancer cell lines [2] with potency in the same range as marketed cytotoxic agents. The compound inhibits phosphorylation of a TTK substrate protein at the kinetochore and induces chromosome missegregation in cell lines and mouse tumors in vivo, demonstrating target engagement.The compound was used to investigate TTK inhibition as a therapeutic approach for TNBC in a xenograft model of the human TNBC cell line MDA-MB-231 and in a mouse model of spontaneous mammary tumor formation based on genetic inactivation of the BRCA1 and TP53 genes [3]. The compound inhibited tumor growth in the MDA-MB-231 xenograft model as a single agent. In the genetic breast cancer model upon co-treatment with docetaxel we observed tumor regression and increase in mouse survival.TTK inhibition is proposed as a novel therapy for the treatment of TNBC.