Phase I Study Of Cfi-402257, An Oral Ttk Inhibitor, In Patients With Advanced Solid Tumors.

TPS2619Background: TTK (MPS1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint (SAC), chromosome alignment and error correction in mitosis. Inhibition of TTK causes premature mitotic exit with unattached chromosomes, resulting in chromosomal missegregation, aneuploidy and cell death. TTK is overexpressed in several tumor types, which may contribute to survival and proliferation of aneuploid cells, and higher expression correlates with adverse outcomes. The Campbell Family Therapeutics Group at the University Health Network (UHN) has developed CFI-402257, a potent (Ki = 0.09 nM, IC50 = 1.2 nM), highly selective and orally active inhibitor of TTK, with negligible activity towards 265 other kinases. Robust suppression of tumor growth was achieved upon oral dosing of single agent CFI-402257 at tolerated doses in several cell line (breast, colorectal) and patient-derived (ovarian) xenograft models. Pharmacodynamic effects including reduction in phospho-histone H3 wer...