Small-molecule TopBP1 inhibitor for breast and ovarian cancers

A small molecule inhibitor of TopBP1, a scaffolding protein that promotes DNA replication and repair, could help treat breast and ovarian cancers by inducing apoptosis and inhibiting oncogenic MYC activity.  

Large-scale molecular docking screening for small molecules that bind to the BRCT7/8 domains of TopBP1 with drug-like properties, no known off-target interactions, and close docking scores, identified 99 compounds that were tested for efficacy in two human breast cancer cell lines. Hit expansion of lead compounds using docking servers identified a methylpyrazole-quinuclidin derivative with modified side chains that were in the desired positions for increased activity, which blocked TopBP1 interactions with an autocatalytic phosphopeptide and the DNA-binding domain of p53 in vitro with an IC50 of 10 nM...