RP-6685

RP-6685, a potent, selective Pol θ inhibitor with an IC50 of 5.8 nM, acts as an ATP-competitive allosteric agent, specifically targeting DNA-bound Polθ. RP6685 exhibits high selectivity toward BRCA-mutated cancer cells, leveraging synthetic lethality and showing in vivo efficacy in an HCT116 BRCA2−/− mouse xenograft model. Oral and intravenous administration of RP 6685 at 50–100 mg/kg BID, with a maximum tolerated dose of 80 mg/kg over 21 days, confirmed favorable pharmacokinetics and bioavailability. In vitro, micromolar-range concentrations are required for cell proliferation inhibition, showing reduced potency compared to enzyme assays, yet effective inhibition of DNA polymerase activity.