PARG inhibitor + USP1 inhibitor

**PARG inhibitor + USP1 inhibitor** is a combination therapy strategy involving inhibitors of poly(ADP-ribose) glycohydrolase (PARG) and ubiquitin-specific peptidase 1 (USP1), two enzymes critical in DNA damage repair pathways. PARG degrades poly(ADP-ribose) (PAR) chains synthesized by PARP enzymes at DNA damage sites, facilitating repair factor dissociation, while USP1 deubiquitinates FANCD2 and other proteins to support homologous recombination (HR) and replication fork protection. Dual inhibition traps PAR chains and disrupts HR/fanconi anemia pathway function, leading to synthetic lethality in HR-deficient (HRD) tumors, such as BRCA1/2-mutant cancers, by elevating unrepaired DNA damage, replication stress, and single-stranded DNA gaps. Preclinical data demonstrate synergistic tumor cell killing, particularly in ovarian cancer and PARPi-resistant models, outperforming PARPi + USP1i combinations in some contexts, with potential to overcome resistance mechanisms like replication fork stabilization.[7][9][10]