DNA polymerase theta inhibitor MOMA-313

An orally bioavailable inhibitor of DNA polymerase (pol) theta helicase, with potential antineoplastic activity. Upon oral administration, DNA polymerase theta inhibitor MOMA-313 specifically targets, binds to and inhibits the pol theta helicase domain and thereby inhibits the activity of pol theta. This prevents pol theta-mediated repair of DNA double-strand breaks (DSBs) via the theta-mediated end joining (TMEJ) process. This causes apoptosis and inhibits proliferation in homologous recombination (HR)-deficient cancer cells. MOMA-313 may have a synergistic effect if administered in combination with a poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor. Pol theta, a DNA helicase-polymerase protein, plays a key role in repair of DNA DSBs through TMEJ and is highly expressed in cancer cells while nearly absent in most healthy tissues. It plays a key role in cancer cell survival. In HR-deficient cancers, DNA DSB repair is impaired and is dependent on pol theta for repair and survival.