RP-2119

**RP-2119** is a potent, selective, and orally bioavailable small molecule inhibitor of **DNA polymerase theta (Polθ)**, an enzyme essential for the microhomology-mediated end joining (MMEJ) pathway in DNA double-strand break repair. Its mechanism targets cancers with homologous recombination deficiencies (e.g., BRCA1/2 mutations), exploiting synthetic lethality. Preclinical studies demonstrated robust in vitro activity in HR-deficient cell lines and synergy with PARP inhibitors such as olaparib in mouse xenograft models, offering a potential combination approach for treating genome instability-related tumors. The compound was advanced through preclinical development by Repare Therapeutics, but was later discontinued preclinically in favor of next-generation Polθ inhibitors[1][2][4][5][9][10].

Other names

RP-2119RP2119RP 2119