Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity

TTK
is an essential spindle assembly checkpoint enzyme in many
organisms. It plays a central role in tumor cell proliferation and
is aberrantly overexpressed in a wide range of tumor types. We recently
reported on a series of potent and selective TTK inhibitors with strong
antiproliferative activity in triple negative breast cancer (TNBC)
cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic
TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked
on a structure-enabled design and optimization campaign to identify
an improved series with excellent potency, TTK selectivity, solubility,
CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model.
These efforts culminated in the discovery of 25 (TTK
IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which
showed significant single-agent efficacy when dosed iv in a TNBC xenograft
model without body weight loss.