RP-2119 (RP2119) is a selective, potent, and bioavailable inhibitor of DNA polymerase theta (Polθ) ATPase inhibitor with IC50 of 0.7 nM (hPOLθ ATPase) in ADP-glo assayss.
RP-2119 exhibits high selectivity over a panel of related ATPases, including HELQ, FANCM, BLM, and WRN (IC50s>10 uM).
RP-2119 shows strong antiproliferative activity in a panel of BRCA2-deficient cancer cell lines with IC50 of 45 and 51 nM for DLD-1 BRCA2–/– (WT) and HCT 116 BRCA2–/– (WT) respectively.
RP-2119 exhibits MMEJ activity IC50 of 54 nM in cellular MMEJ reporter assay.
RP-2119 potently inhibiting the ATPase function of the helicase-like domain of Polθ across both human and preclinical species with IC50 of <2.5/<3/<3/<1.5/<5 nM for mouse/ rat / dog / pig / chimpanzee POLθ ATPase domain in ADP-glo assays.
RP-2119 displays synergistic cytotoxicity in HCT 116 BRCA2–/– cells, leading to a pronounced loss of cell viability, when combined with PARP inhibitor olaparib, in HR-deficient cell line- and patient-derived mouse xenografts.