The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen

Triple
negative breast cancer (TNBC) remains a serious unmet medical
need with discouragingly high relapse rates. We report here the synthesis
and structure–activity relationship (SAR) of a novel series
of 2,4,5-trisubstituted-7H-pyrrolo­[2,3-d]­pyrimidines with potent activity against TNBC tumor cell lines.
These compounds were discovered from a TNBC phenotypic screen and
possess a unique dual inhibition profile targeting TTK (mitotic exit)
and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC
tumor cell assay, identified potent and selective compounds with favorable
in vitro and in vivo activity profiles and good iv PK properties.
This cell-based driven SAR produced compounds with strong single agent
in vivo efficacy in multiple TNBC xenograft models without significant
body weight loss. These data supported the nomination of CC-671 into
IND-enabling studies as a single agent TNBC therapy.