RP-2119

Further optimization of potency and ADME properties led to the identification of RP-2119 with robust in vitro cellular activity in a wide range of HR-deficient cancer cell lines. In HR-deficient cell line- and patient-derived mouse xenografts, RP-2119 demonstrated strong synergy with the PARP inhibitor, olaparib, without exacerbating its hematological toxicity.

A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2 mouse tumor xenograft model.