RTx-303

RTx-303 is an orally bioavailable, selective, small-molecule allosteric inhibitor of DNA polymerase theta (Polθ, encoded by the *POLQ* gene). Developed by Recombination Therapeutics, a spin-out of Thomas Jefferson University, RTx-303 targets the polymerase domain of Polθ (Polθ-pol). Polθ is a multi-functional DNA repair factor essential for microhomology-mediated end-joining (MMEJ) / theta-mediated end-joining (TMEJ), a backup double-strand break repair pathway that homologous recombination-deficient (HRD) cancer cells (such as those with BRCA1/2 mutations) rely on for survival. By inhibiting Polθ, RTx-303 induces synthetic lethality in HRD tumors while sparing normal cells. In preclinical models, RTx-303 has demonstrated robust in vivo efficacy, high oral bioavailability, and strong synergy when combined with PARP inhibitors, radiation, and chemotherapy, effectively overcoming treatment resistance.

Other names

Polθ inhibitor