Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy

Triple
negative breast cancer (TNBC) is an aggressive disease with
high relapse rates and few treatment options. Outlined in previous
publications, we identified a series of potent, dual TTK/CLK2 inhibitors
with strong efficacy in TNBC xenograft models. Pharmacokinetic properties
and kinome selectivity were optimized, resulting in the identification
of a new series of potent, selective, and orally bioavailable TTK
inhibitors. We describe here the structure–activity relationship
of the 2,4-disubstituted-7H-pyrrolo­[2,3-d]­pyrimidine series, leading to significant single agent efficacy
in a TNBC xenograft model without body weight loss. The design effort
evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable
TTK inhibitor is described.