Poly(ADP-ribose) glycohydrolase (PARG), the principal enzyme responsible for degradation of poly(ADP-ribose) chains, has emerged as a promising therapeutic target in oncology. However, its extended, solvent-exposed catalytic pocket presents a challenging target for small-molecule drug discovery.

To address this challenge, we pursued reversible and covalent PARG inhibitor strategies in parallel. Optimization of reversible inhibitors revealed an unexpectedly strong influence of scaffold architecture on potency, driven by key π–π interactions within the catalytic pocket. Subsequent optimization of physicochemical and metabolic properties culminated in the discovery of FORX-428, a potent and selective reversible PARG inhibitor with strong activity in PARG-sensitive tumor models that entered clinical evaluation in 2025.

In parallel, the long half-life of PARG and the proximity of Cys872 to the inhibitor-binding site motivated a covalent approach. Structure-guided design, scaffold hopping, and exploration of different covalent warheads, including underexplored bicyclo[1.1.0]butane-derived motifs, led to the discovery of the first covalent PARG inhibitors.

This presentation will highlight the medicinal chemistry strategies, key learnings, and trade-offs encountered along these two complementary paths to PARG inhibition.