Poly (ADP-ribose) glycohydrolase (PARG)

Poly (ADP-ribose) polymerase inhibitors (PARPi) were the first clinically approved drugs to exploit synthetic lethality in cancer treatment, particularly in tumors with homologous recombination deficiencies (HRD). However, many tumors develop resistance to PARPi, often by restoring homologous recombination capacity, highlighting the need for new approaches to treat HR-deficient cancers.

Poly (ADP-ribose) glycohydrolase (PARG) offers a promising complementary target. PARG plays a critical role in the DNA damage response by degrading PAR chains generated by PARP1/2 activity, thereby contributing to the dissociation of DNA repair complexes from chromatin. Inhibiting PARG may enhance synthetic-lethality-based treatment strategies and support the development of new therapies for HR-deficient cancers.